Aminopyrimidine kinase inhibitors

ABSTRACT

Disclosed are compounds, pharmaceutical compositions containing those compounds, and uses of the compounds and compositions as modulators of CK1, CK1γ1, CK1γ2, CKlγ3, CK2, Pim 1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, the AKT pathway, and/or the mTOR pathway. Uses are also disclosed for the treatment or prevention of a range of therapeutic indications due at least in part to aberrant physiological activity of CK1, CK1γ1, CK1γ2, CKlγ3, CK2, Pim 1, Pim2, Pim3, the TGFβ pathway, the Wnt pathway, the JAK/STAT pathway, the AKT pathway, and/or the mTOR pathway.

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application Ser. No. 61/555,617, filed Nov. 4, 2011.

BACKGROUND OF THE INVENTION

Casein kinase 1 (CK1) is a family of evolutionarily conservedserine/threonine kinases including seven known members in vertebrates(CK1α, -β, -γ1, -γ2, -γ3, -δ and -ε). The CK1s contain a typical kinasedomain followed by a C-terminal tail region, which has been implicatedin the regulation of CK1 localization, substrate selectivity and kinaseactivity. Myriad proteins have been found to be phosphorylated by CK1s,which are involved in a wide range of cellular functions includingvesicular trafficking, DNA damage repair, cell cycle progression,cytokinesis and circadian rhythms (reviewed by Gross and Anderson (1998)Cell Signal 10:699-711; Vielhaber and Virshup (2001) IUBMB Life 51:73-8;Knippschild et al. (2005) Cell Signal 17:675-89). Moreover, CK1 familymembers (-α, -δ/ε and -γ) modulate the activities of major signalingpathways (for example, Wnt and Shh) through several mechanisms (Peterset al. (1999) Nature 401:345-50; Liu et al. (2002); Price and Kalderon(2002) Cell 108:823-35; Davidson et al. (2005) Nature 438:867-72; Zenget al. (2005) Nature 438:873-7; and reviewed by Price (2006) Genes Dev20:399-410).

In mammals seven CK1 isoforms, namely CK1α, β, γ₁₋₃, δ and ε, andseveral splice variants have been described. They all contain a highlyconserved kinase domain, a short N-terminal domain of 6 to 76 aminoacids and a highly variable C-terminal domain of 24 to more than 200amino acids. The constitutive phosphotransferase activity of CK1isoforms is tightly controlled by several mechanisms. For example, theclosely related isoforms CK18 and E, which share a 98% identity at theamino acid level in their catalytic domain, are regulated byautophosphorylation, dephosphorylation and proteolytic cleavage. Membersof the CK1 family are found in the nucleus, the cytoplasm and in theplasma membrane. By phosphorylating many different substrates bearingeither a canonical or non-canonical consensus sequence they modulate theactivity of key regulator proteins involved in many cellular processessuch as cell differentiation, cell proliferation, apoptosis, circadianrhythm, chromosome segregation, and vesicle transport.

The Pim kinase family contains three isoforms, Pim-1, Pim-2 and Pim-3,and has recently emerged as targets of interest in oncology and immuneregulation. Ongoing studies have identified a role for these proteins incell survival and proliferation, both functionally and mechanistically,and overexpression has been observed in a number of human cancers andinflammatory states.

Pim kinases suppress apoptosis and regulate cell-cycle progression.Elevated levels of Pim kinases have been reported in solid tumors suchas prostate cancer and pancreatic cancer. Pim-1 was initially discoveredin murine leukemia and several independent studies have shown thiskinase to be upregulated in human prostate cancer. Pim-1, 2 and 3 makeup a distinct and highly homologous family of serine/threonine kinasesbelonging to the calmodulin-dependent protein kinase-related (CAMK)family. In addition to the three gene-encoded proteins, translationalvariants have also been reported for Pim-1 and 2 resulting fromutilization of alternative start codons. The name Pim refers to theoriginal identification of the pim-1 gene as a frequent proviralinsertion site in Moloney murine leukemia virus-induced T-celllymphomas, and the gene encoding Pim-2 was subsequently found to havesimilar susceptibility. Pim-3, originally designated kinase induced bydepolarization (KID)-1, was later renamed due to high sequencesimilarity to Pim-1 (71% identity at the amino acid level). Consideringall three isoforms, Pim proteins are widely expressed with high levelsin hematopoietic tissue and are aberrantly expressed in a variety ofhuman malignancies. Pim kinases positively regulate cell survival andproliferation, affording therapeutic opportunities in oncology. The Pimprotein kinases are frequently overexpressed in prostate cancer andcertain forms of leukemia and lymphoma. A role has been described forPim-1 in human pancreatic ductal adenocarcinoma (PDAC), and Pim-1 kinasehas been identified as a potential molecular marker for mutated K-Rasactivity. Pim-2 is rapidly becoming an increasingly interesting targetfor multiple myeloma. Rapamycin combined with Pim-2 silencing, or Piminhibitors combined with PI3K inhibitors have been found tocooperatively enhance multiple myeloma cell death, suggestingindependent pathways with common substrates. Further, it has been shownthat PIM kinase expression can affect the clinical outcome of lymphomachemotherapy.

A role for Pim kinases in immune regulation has also been observed.Pim-2 has been reported to have enhanced levels of expression in avariety of inflammatory states and may function as a positive regulatorof interleukin-6 (IL-6), whereby overexpression of the kinase augmentsstimulus-induced IL-6 levels. Pim-1 and 2 have also been implicated incytokine-induced T-cell growth and survival. Comparing the sensitivityof stimulated T cells from Pim-1−/−Pim-2−/− mice to wild-type micefollowing treatment with the immunosuppressant rapamycin, it was foundthat T-cell activation was significantly impaired by Pim-1/Pim-2deficiency, suggesting that Pim kinases promote lymphocyte growth andsurvival through a PI3K/AKT (PKB, protein kinase B)/mammalian target ofrapamycin (mTOR)-independent pathway. Other parallel but independentfunctions and overlapping substrate specificity for proteins in thesepathways have been reported as well, including the positive regulationof transcription of nuclear factor kappa-B (NF-κB)-responsive genes,which have implications in both inflammation and oncology. Therefore,Pim kinases are attractive targets for both therapeutic areas. Further,Pim kinases have been reported to play a role in the protection of theATP-binding cassette (ABC) transporter P-glycoprotein (Pgp; ABCB1) fromproteolytic and proteasomal degradation. Pgp is known to mediate drugefflux and as such, inhibitors of Pim kinases may provide a novelapproach to abrogating drug resistance.

SUMMARY OF THE INVENTION

An aspect of the present invention relates to compounds that inhibitcasein kinase 1 and/or casein kinase 2 and/or a PIM kinase. For example,an embodiment relates to a compound of formula 1 or a pharmaceuticallyacceptable salt thereof:

wherein independently for each occurrence

-   -   X is —N(R₇)₂, —N(R₇)(R₂), or —N(H)—R₃-R₆;    -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;    -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,        —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;    -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;    -   R₅ is selected from the group consisting of 1,4-cyclohexanediyl,        1,4-phenylene, 1,4-cycloheptanediyl, 1,4-cyclooctanediyl,        1,5-cyclooctanediyl, 1,4-bicyclo[2.2.1]heptanediyl,        1,4-bicyclo[2.2.2]octanediyl, and 1,5-bicyclo[3.3.1]nonanediyl;    -   R₆ is selected from the group consisting of alkyl, alkylaryl,        aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of        which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of alkyl, alkylaryl, aralkyl, aryl, heteroaryl,        alkoxy, hydroxy, perfluoroalkyl, trifluoromethoxy, and halide,        wherein the optional aryl or heteroaryl substituent may be        optionally substituted with alkyl, halide, alkoxy,        perfluoroalkyl, or dioxolanyl;    -   R₇ is selected from the group consisting of H, —C(═NR)R,        —(C(R)₂)_(n)R, alkyl, alkylaryl, aryl, alkylheteroaryl,        alkylheteroalkyl, and heteroaryl, any of which is optionally        mono or di-substituted, and the substituents, if present, are        independently selected from the group consisting of alkyl,        alkylaryl, aralkyl, aryl, heteroaryl, alkoxy, hydroxy,        perfluoroalkyl, trifluoromethoxy, and halide, wherein the        optional aryl or heteroaryl substituent may be optionally        substituted with alkyl, halide, alkoxy, perfluoroalkyl, or        dioxolanyl, or    -   two instances of R₇ and the nitrogen to which they are bonded        taken together represent a nitrogen-containing heterocyclyl,        optionally containing one additional heteroatom in the ring,        wherein said additional heteroatom is selected from the group        consisting of —O—, —N(R)—, and —S—;    -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl;    -   R is H or (C₁-C₄)alkyl; and    -   n is 1, 2 or 3.

One aspect of the invention is a compound of formula 2 or apharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   X is —N(R₇)₂, —N(R₇)(R₂), or —N(H)—R₃-R₄;    -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;    -   R₁ is selected from the group consisting of 1,4-cyclohexanediyl        and 1,4-phenylene;    -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,        —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;    -   R₃ is —C(═NR)— or —(C(R)₂)₈—;    -   R₄ is selected from the group consisting of aryl and heteroaryl,        either of which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of halide, alkyl, perfluoroalkyl, aryl,        heteroaryl, and heterocyclyl; wherein the optional aryl or        heteroaryl substituent is itself optionally substituted with        perfluoroalkyl or dioxolane;    -   R₇ is selected from the group consisting of H, —C(═NR)R,        —(C(R)₂)_(n)R, alkyl, alkylaryl, aryl, alkylheteroaryl,        alkylheteroalkyl, and heteroaryl, any of which is optionally        mono or di-substituted, and the substituents, if present, are        independently selected from the group consisting of alkyl,        alkylaryl, aralkyl (including but not limited to benzyl), aryl        (including but not limited to phenyl), heteroaryl (including but        not limited to pyridyl, imidazolyl, thiazolyl, furyl, and        thionyl), alkoxy (including but not limited to methoxy),        hydroxy, perfluoroalkyl (including but not limited to        trifluoromethyl), trifluoromethoxy, and halide (including but        not limited to fluoride and chloride), wherein the optional aryl        or heteroaryl substituent may be optionally substituted with        alkyl, halide, alkoxy, perfluoroalkyl, or dioxolanyl, or    -   two instances of R₇ and the nitrogen to which they are bonded        taken together represent a nitrogen-containing heterocyclyl,        optionally containing one additional heteroatom in the ring,        wherein said additional heteroatom is selected from the group        consisting of —O—, —N(R)—, and —S—;    -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl;    -   R is H or (C₁-C₄)alkyl; and    -   n is 1, 2 or 3.

Another embodiment relates to a compound of formula 3 or apharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,        —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;    -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;    -   R is H or (C₁-C₄)alkyl;    -   n is 1, 2 or 3;    -   R₆ is selected from the group consisting of alkyl, alkylaryl,        aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of        which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of alkyl, alkylaryl, aralkyl (including but not        limited to benzyl), aryl (including but not limited to phenyl),        heteroaryl (including but not limited to pyridyl, imidazolyl,        thiazolyl, furyl, and thionyl), alkoxy (including but not        limited to methoxy), hydroxy, perfluoroalkyl (including but not        limited to trifluoromethyl), trifluoromethoxy, and halide        (including but not limited to fluoride and chloride), wherein        the optional aryl or heteroaryl substituent may be optionally        substituted with alkyl, halide, alkoxy, perfluoroalkyl, or        dioxolanyl; and    -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

Another embodiment relates to a compound of formula 4 or apharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;    -   R is H or (C₁-C₄)alkyl;    -   n is 1, 2 or 3; and    -   R₄ is selected from the group consisting of aryl and heteroaryl,        either of which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of halide, alkyl, perfluoroalkyl, aryl,        heteroaryl, and heterocyclyl; wherein the optional aryl or        heteroaryl substituent is itself optionally substituted with        perfluoroalkyl or dioxolane.

Another embodiment relates to a compound of formula 5 or apharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;    -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,        —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;    -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;    -   R is H or (C₁-C₄)alkyl;    -   n is 1, 2 or 3;    -   R₆ is selected from the group consisting of alkyl, alkylaryl,        aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of        which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of alkyl, alkylaryl, aralkyl (including but not        limited to benzyl), aryl (including but not limited to phenyl),        heteroaryl (including but not limited to pyridyl, imidazolyl,        thiazolyl, furyl, and thionyl), alkoxy (including but not        limited to methoxy), hydroxy, perfluoroalkyl (including but not        limited to trifluoromethyl), trifluoromethoxy, and halide        (including but not limited to fluoride and chloride), wherein        the optional aryl or heteroaryl substituent may be optionally        substituted with alkyl, halide, alkoxy, perfluoroalkyl, or        dioxolanyl; and    -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

Another embodiment relates to a compound of formula 6 or apharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;    -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,        —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;    -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;    -   R is H or (C₁-C₄)alkyl;    -   n is 1, 2 or 3;    -   R₆ is selected from the group consisting of alkyl, alkylaryl,        aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of        which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of alkyl, alkylaryl, aralkyl (including but not        limited to benzyl), aryl (including but not limited to phenyl),        heteroaryl (including but not limited to pyridyl, imidazolyl,        thiazolyl, furyl, and thionyl), alkoxy (including but not        limited to methoxy), hydroxy, perfluoroalkyl (including but not        limited to trifluoromethyl), trifluoromethoxy, and halide        (including but not limited to fluoride and chloride), wherein        the optional aryl or heteroaryl substituent may be optionally        substituted with alkyl, halide, alkoxy, perfluoroalkyl, or        dioxolanyl; and    -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of CK1, CK1γ1, CK1γ2, or CK1γ3. Inone embodiment the compound has an IC₅₀ of less than about 5000 nM forCK1, CK1γ1, CK1γ2, or CK1γ3. In one embodiment the compound has an IC₅₀of less than about 1000 nM for CK1, CK1γ1, CK1γ2, or CK1γ3. In oneembodiment the compound has an IC₅₀ of less than about 500 nM for CK1,CK1γ1, CK1γ2, or CK1γ3.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of CK2. In one embodiment thecompound has an IC₅₀ of less than about 5000 nM for CK2. In oneembodiment the compound has an IC₅₀ of less than about 1000 nM for CK2.In one embodiment the compound has an IC₅₀ of less than about 500 nM forCK2.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of PIM1, PIM2, or PIM3. In oneembodiment the compound has an IC₅₀ of less than about 5000 nM for PIM1,PIM2, or PIM3. In one embodiment the compound has an IC₅₀ of less thanabout 1000 nM for PIM1, PIM2, or PIM3. In one embodiment the compoundhas an IC₅₀ of less than about 500 nM for PIM1, PIM2, or PIM3.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of the Wnt pathway.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of the TGFβ pathway.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of the JAK/STAT pathway.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of the mTOR pathway.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is an inhibitor of the AKT pathway.

An embodiment relates to any one of the aforementioned compounds,wherein the compound is a modulator of Pgp degradation, drug efflux, ordrug resistance.

An embodiment relates to a pharmaceutical composition comprising any oneor combination of the aforementioned compounds, and a pharmaceuticallyacceptable carrier.

Another embodiment relates to a method of inhibiting CK1 activity,comprising contacting CK1, CK1γ1, CK1γ2, or CK1γ3 with any one of theaforementioned compounds.

Another embodiment relates to a method of inhibiting CK2 activity,comprising contacting CK2 with any one of the aforementioned compounds.

Another embodiment relates to a method of treating or preventing acondition associated with aberrant CK1, CK1γ1, CK1γ2, or CK1γ3 activity,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating or preventing acondition associated with aberrant CK2 activity, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating cancer, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of any one of the aforementioned compounds or pharmaceuticalcompositions. In one embodiment the cancer is a cancer of a systemselected from the group consisting of the hematopoietic system, immunesystem, endocrine system, pulmonary system, gastrointestinal system,musculoskeletal system, reproductive system, central nervous system, andurologic system. In one embodiment the cancer is located in the mammal'smyeloid tissues, lymphoid tissues, pancreatic tissues, thyroid tissues,lung tissues, colon tissues, rectal tissues, anal tissues, livertissues, skin, bone, ovarian tissues, uterine tissues, cervical tissues,breast, prostate, testicular tissues, brain, brainstem, meningealtissues, kidney or bladder. In one embodiment the cancer is selectedfrom the group consisting of breast cancer, colon cancer, multiplemyeloma, prostate cancer, Hodgkin's lymphoma, non-Hodgkin's lymphoma,leukemia, hematologic malignancy, renal cell carcinoma, renal cancer,malignant melanoma, pancreatic cancer, lung cancer, colorectalcarcinoma, brain cancer, head and neck cancer, bladder cancer, thyroidcancer, ovarian cancer, cervical cancer, and myelodysplastic syndrome.

Another embodiment relates to a method of treating leukemia, multiplemyeloma, or other hematologic malignancies, comprising administering toa mammal in need thereof a therapeutically effective amount of any oneof the aforementioned compounds.

Another embodiment relates to a method of treating Alzheimer's disease,comprising administering to a mammal in need thereof a therapeuticallyeffective amount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating a Wnt-dependentdisease, comprising administering to a mammal in need thereof atherapeutically effective amount of any one of the aforementionedcompounds.

Another embodiment relates to a method of treating a TGFβ-dependentdisease, comprising administering to a mammal in need thereof atherapeutically effective amount of any one of the aforementionedcompounds.

Another embodiment relates to a method of treating a JAK/STAT-dependentdisease, comprising administering to a mammal in need thereof atherapeutically effective amount of any one of the aforementionedcompounds.

Another embodiment relates to a method of treating an mTOR-dependentdisease, comprising administering to a mammal in need thereof atherapeutically effective amount of any one of the aforementionedcompounds.

Another embodiment relates to a method of treating an AKT-dependentdisease, comprising administering to a mammal in need thereof atherapeutically effective amount of any one of the aforementionedcompounds.

Another embodiment relates to a method of treating or preventinginflammation, inflammatory diseases (e.g., osteoarthritis and rheumatoidarthritis), neurological conditions (e.g., Alzheimer's disease) andneurodegeneration, comprising administering to a mammal in need thereofa therapeutically effective amount of any one of the aforementionedcompounds.

Another embodiment relates to a method of treating or preventingbone-related diseases and conditions, including osteoporosis and boneformation, or facilitating bone restoration, comprising administering toa mammal in need thereof a therapeutically effective amount of any oneof the aforementioned compounds.

Another embodiment relates to a method of treating or preventinghypoglycemia, metabolic syndrome and diabetes, comprising administeringto a mammal in need thereof a therapeutically effective amount of anyone of the aforementioned compounds.

Another embodiment relates to a method of influencing apoptosis (e.g.,increasing the rate of apoptosis in cancerous cells), comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of any one of the aforementioned compounds.

Another embodiment relates to a method of treating or preventingaberrant embryonic development, comprising administering to a mammal inneed thereof a therapeutically effective amount of any one of theaforementioned compounds.

Another embodiment relates to a method of inhibiting PIM activity,comprising contacting PIM1, PIM2 or PIM3 with any one of theaforementioned compounds.

Another embodiment relates to a method for treating or preventing acondition associated with aberrant PIM activity, comprisingadministering to a mammal in need thereof a therapeutically effectiveamount of any one of the aforementioned compounds.

Another embodiment relates to a method of modulating Pgp degradationand/or drug efflux activity, comprising contacting a cell with any oneof the aforementioned compounds.

Another embodiment relates to a method for treating a malignancy basedupon modulation of Pgp, comprising administering to a mammal in needthereof a therapeutically effective amount of any one of theaforementioned compounds.

Another embodiment relates to a method for treating a malignancycomprising co-administering to a mammal in need thereof atherapeutically effective amount of any one of the aforementionedcompounds and a therapeutically effective amount of a known chemotherapyor kinase inhibitor (including but not limited to a PI3K inhibitor, amTOR inhibitor, or an AKT inhibitor).

DETAILED DESCRIPTION OF THE INVENTION Definitions

The definitions of terms used herein are meant to incorporate thepresent state-of-the-art definitions recognized for each term in thechemical and pharmaceutical fields. Where appropriate, illustration isprovided. The definitions apply to the terms as they are used throughoutthis specification, unless otherwise limited in specific instances,either individually or as part of a larger group.

Where stereochemistry is not specifically indicated, all stereoisomersof the inventive compounds are included within the scope of theinvention, as pure compounds as well as mixtures thereof. Unlessotherwise indicated, individual enantiomers, diastereomers, geometricalisomers, and combinations and mixtures thereof are all encompassed bythe present invention. Polymorphic crystalline forms and solvates arealso encompassed within the scope of this invention.

As used herein, the term “isolated” in connection with a compound of thepresent invention means the compound is not in a cell or organism andthe compound is separated from some or all of the components thattypically accompany it in nature.

As used herein, the term “pure” in connection with an isolated sample ofa compound of the present invention means the isolated sample containsat least 60% by weight of the compound. In certain embodiments, theisolated sample contains at least 70% by weight of the compound. Incertain embodiments, the isolated sample contains at least 80% by weightof the compound. In certain embodiments, the isolated sample contains atleast 90% by weight of the compound. In certain embodiments, theisolated sample contains at least 95% by weight of the compound. Thepurity of an isolated sample of a compound of the present invention maybe assessed by a number of methods or a combination of them; e.g.,thin-layer, preparative, or flash chromatography, mass spectrometry,HPLC, NMR analysis, and the like.

The term “heteroatom” is art-recognized and refers to an atom of anyelement other than carbon or hydrogen. Illustrative heteroatoms includeboron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term “alkyl” is art-recognized, and includes saturated aliphaticgroups, including straight-chain alkyl groups, branched-chain alkylgroups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkylgroups, and cycloalkyl substituted alkyl groups. In certain embodiments,a straight chain or branched chain alkyl has about 30 or fewer carbonatoms in its backbone (e.g., C₁-C₃₀ for straight chain, C₃-C₃₀ forbranched chain), and alternatively, about 20 or fewer. Likewise,cycloalkyls have from about 3 to about 10 carbon atoms in their ringstructure, and alternatively about 5, about 6, or about 7 carbons in thering structure.

Unless the number of carbons is otherwise specified, “lower alkyl”refers to an alkyl group, as defined above, but having from one to aboutten carbons, alternatively from one to about six carbon atoms in itsbackbone structure. Likewise, “lower alkenyl” and “lower alkynyl” havesimilar chain lengths.

The term “aralkyl” is art-recognized and refers to an alkyl groupsubstituted with an aryl group (e.g., an aromatic or heteroaromaticgroup).

The terms “alkenyl” and “alkynyl” are art-recognized and refer tounsaturated aliphatic groups analogous in length and possiblesubstitution to the alkyls described above, but that contain at leastone double or triple bond respectively.

The term “aryl” is art-recognized and refers to 5-, 6- and 7-memberedsingle-ring aromatic groups that may include from zero to fourheteroatoms, for example, benzene, naphthalene, anthracene, pyrene,pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole,pyrazole, pyridine, pyrazine, pyridazine and pyrimidine, and the like.Those aryl groups having heteroatoms in the ring structure may also bereferred to as “aryl heterocycles” or “heteroaromatics.” The aromaticring may be substituted at one or more ring positions with suchsubstituents as described above, for example, halogen, azide, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, sulfonamido, ketone, aldehyde, ester,heterocyclyl, aromatic or heteroaromatic moieties, —CF₃, —CN, or thelike. The term “aryl” also includes polycyclic ring systems having twoor more cyclic rings in which two or more carbons are common to twoadjoining rings (the rings are “fused rings”) wherein at least one ofthe rings is aromatic, e.g., the other cyclic rings may be cycloalkyls,cycloalkenyls, cycloalkynyls, aryls and/or heterocyclyls.

The terms ortho, meta and para are art-recognized and refer to 1,2-,1,3- and 1,4-disubstituted benzenes, respectively. For example, thenames 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The terms “heterocyclyl”, “heteroaryl”, or “heterocyclic group” areart-recognized and refer to 3- to about 10-membered ring structures,alternatively 3- to about 7-membered rings, whose ring structuresinclude one to four heteroatoms. Heterocycles may also be polycycles.Heterocyclyl groups include, for example, thiophene, thianthrene, furan,pyran, isobenzofuran, chromene, xanthene, phenoxanthene, pyrrole,imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine,pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine,quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine,quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline,phenanthridine, acridine, pyrimidine, phenanthroline, phenazine,phenarsazine, phenothiazine, piperonyl, furazan, phenoxazine,pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine,morpholine, lactones, lactams such as azetidinones and pyrrolidinones,sultams, sultones, and the like. The heterocyclic ring may besubstituted at one or more positions with such substituents as describedabove, as for example, halogen, alkyl, aralkyl, alkenyl, alkynyl,cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido,phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio,sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic orheteroaromatic moiety, —CF₃, —CN, or the like.

The term “optionally substituted” refers to a chemical group, such asalkyl, cycloalkyl aryl, and the like, wherein one or more hydrogen maybe replaced with a substituent as described herein, including but notlimited to halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl,hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate,phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl,sulfonamido, ketone, aldehyde, ester, heterocyclyl, aromatic orheteroaromatic moieties, —CF₃, —CN, or the like.

The terms “polycyclyl” or “polycyclic group” are art-recognized andrefer to two or more rings (e.g., cycloalkyls, cycloalkenyls,cycloalkynyls, aryls and/or heterocyclyls) in which two or more carbonsare common to two adjoining rings, e.g., the rings are “fused rings”.Rings that are joined through non-adjacent atoms are termed “bridged”rings. Each of the rings of the polycycle may be substituted with suchsubstituents as described above, as for example, halogen, alkyl,aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro,sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl,silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, aheterocyclyl, an aromatic or heteroaromatic moiety, —CF₃, —CN, or thelike.

The term “carbocycle” is art-recognized and refers to an aromatic ornon-aromatic ring in which each atom of the ring is carbon.

The term “nitro” is art-recognized and refers to —NO₂.

The term “halogen” is art-recognized and refers to —F, —Cl, —Br or —I.

“Halide” designates the corresponding anion of the halogens, and“pseudohalide” has the definition set forth on page 560 of AdvancedInorganic Chemistry by Cotton and Wilkinson.

The term “sulfhydryl” is art-recognized and refers to —SH.

The term “hydroxyl” means —OH.

The term “sulfonyl” is art-recognized and refers to —SO₂ ⁻.

The terms “amine” and “amino” are art-recognized and refer to bothunsubstituted and substituted amines, e.g., a moiety that may berepresented by the general formulas:

wherein R50, R51 and R52 each independently represent a hydrogen, analkyl, an alkenyl, —(CH₂)_(m)—R61, or R50 and R51, taken together withthe N atom to which they are attached complete a heterocycle having from4 to 8 atoms in the ring structure; R61 represents an aryl, acycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zeroor an integer in the range of 1 to 8. In other embodiments, R50 and R51(and optionally R52) each independently represent a hydrogen, an alkyl,an alkenyl, or —(CH₂)_(m)—R61. Thus, the term “alkylamine” includes anamine group, as defined above, having a substituted or unsubstitutedalkyl attached thereto, i.e., at least one of R50 and R51 is an alkylgroup.

The term “acylamino” is art-recognized and refers to a moiety that maybe represented by the general formula:

wherein R50 is as defined above, and R54 represents a hydrogen, analkyl, an alkenyl or —(CH₂)_(m)—R61, where m and R61 are as definedabove.

The term “amido” is art recognized as an amino-substituted carbonyl andincludes a moiety that may be represented by the general formula:

wherein R50 and R51 are as defined above. Certain embodiments of theamide in the present invention will not include imides which may beunstable.

The term “alkylthio” refers to an alkyl group, as defined above, havinga sulfur radical attached thereto. In certain embodiments, the“alkylthio” moiety is represented by one of —S-alkyl, —S-alkenyl,—S-alkynyl, and —S—(CH₂)_(m)—R61, wherein m and R61 are defined above.Representative alkylthio groups include methylthio, ethylthio, and thelike.

The term “carboxyl” is art recognized and includes such moieties as maybe represented by the general formulas:

wherein X50 is a bond or represents an oxygen or a sulfur, and R55 andR56 represents a hydrogen, an alkyl, an alkenyl, —(CH₂)_(m)—R61 or apharmaceutically acceptable salt, R56 represents a hydrogen, an alkyl,an alkenyl or —(CH₂)_(m)—R61, where m and R61 are defined above. WhereX50 is an oxygen and R55 or R56 is not hydrogen, the formula representsan “ester”. Where X50 is an oxygen, and R55 is as defined above, themoiety is referred to herein as a carboxyl group, and particularly whenR55 is a hydrogen, the formula represents a “carboxylic acid”. Where X50is an oxygen, and R56 is hydrogen, the formula represents a “formate”.In general, where the oxygen atom of the above formula is replaced bysulfur, the formula represents a “thiolcarbonyl” group. Where X50 is asulfur and R55 or R56 is not hydrogen, the formula represents a“thiolester.” Where X50 is a sulfur and R55 is hydrogen, the formularepresents a “thiolcarboxylic acid.” Where X50 is a sulfur and R56 ishydrogen, the formula represents a “thiolformate.” On the other hand,where X50 is a bond, and R55 is not hydrogen, the above formularepresents a “ketone” group. Where X50 is a bond, and R55 is hydrogen,the above formula represents an “aldehyde” group.

The term “carbamoyl” refers to —O(C═O)NRR′, where R and R′ areindependently H, aliphatic groups, aryl groups or heteroaryl groups.

The term “oxo” refers to a carbonyl oxygen (═O).

The terms “oxime” and “oxime ether” are art-recognized and refer tomoieties that may be represented by the general formula:

wherein R75 is hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl,aralkyl, or —(CH₂)_(m)—R61. The moiety is an “oxime” when R is H; and itis an “oxime ether” when R is alkyl, cycloalkyl, alkenyl, alkynyl, aryl,aralkyl, or —(CH₂)_(m)—R61.

The terms “alkoxyl” or “alkoxy” are art-recognized and refer to an alkylgroup, as defined above, having an oxygen radical attached thereto.Representative alkoxyl groups include methoxy, ethoxy, propyloxy,tert-butoxy and the like. An “ether” is two hydrocarbons covalentlylinked by an oxygen. Accordingly, the substituent of an alkyl thatrenders that alkyl an ether is or resembles an alkoxyl, such as may berepresented by one of —O-alkyl, —O-alkenyl, —O-alkynyl,—O—(CH₂)_(m)—R61, where m and R61 are described above.

The term “sulfonate” is art recognized and refers to a moiety that maybe represented by the general formula:

in which R57 is an electron pair, hydrogen, alkyl, cycloalkyl, or aryl.

The term “sulfate” is art recognized and includes a moiety that may berepresented by the general formula:

in which R57 is as defined above.

The term “sulfonamido” is art recognized and includes a moiety that maybe represented by the general formula:

in which R50 and R56 are as defined above.

The term “sulfamoyl” is art-recognized and refers to a moiety that maybe represented by the general formula:

in which R50 and R51 are as defined above.

The term “sulfonyl” is art-recognized and refers to a moiety that may berepresented by the general formula:

in which R58 is one of the following: hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, heterocyclyl, aryl or heteroaryl.

The term “sulfoxido” is art-recognized and refers to a moiety that maybe represented by the general formula:

in which R58 is defined above.

The term “phosphoryl” is art-recognized and may in general berepresented by the formula:

wherein Q50 represents S or O, and R59 represents hydrogen, a loweralkyl or an aryl. When used to substitute, e.g., an alkyl, thephosphoryl group of the phosphorylalkyl may be represented by thegeneral formulas:

wherein Q50 and R59, each independently, are defined above, and Q51represents O, S or N. When Q50 is S, the phosphoryl moiety is a“phosphorothioate”.

The term “phosphoramidite” is art-recognized and may be represented inthe general formulas:

wherein Q51, R50, R51 and R59 are as defined above.

The term “phosphonamidite” is art-recognized and may be represented inthe general formulas:

wherein Q51, R50, R51 and R59 are as defined above, and R60 represents alower alkyl or an aryl.

Analogous substitutions may be made to alkenyl and alkynyl groups toproduce, for example, aminoalkenyls, aminoalkynyls, amidoalkenyls,amidoalkynyls, iminoalkenyls, iminoalkynyls, thioalkenyls, thioalkynyls,carbonyl-substituted alkenyls or alkynyls.

The definition of each expression, e.g., alkyl, m, n, and the like, whenit occurs more than once in any structure, is intended to be independentof its definition elsewhere in the same structure.

The terms triflyl, tosyl, mesyl, and nonaflyl are art-recognized andrefer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl,and nonafluorobutanesulfonyl groups, respectively. The terms triflate,tosylate, mesylate, and nonaflate are art-recognized and refer totrifluoromethanesulfonate ester, p-toluenesulfonate ester,methanesulfonate ester, and nonafluorobutanesulfonate ester functionalgroups and molecules that contain said groups, respectively.

The abbreviations Me, Et, Ph, Tf, Nf, Ts, and Ms represent methyl,ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl,p-toluenesulfonyl and methanesulfonyl, respectively. A morecomprehensive list of the abbreviations utilized by organic chemists ofordinary skill in the art appears in the first issue of each volume ofthe Journal of Organic Chemistry; this list is typically presented in atable entitled “Standard List of Abbreviations.”

Certain compounds contained in compositions of the present invention mayexist in particular geometric or stereoisomeric forms. In addition,polymers of the present invention may also be optically active. Thepresent invention contemplates all such compounds, including cis- andtrans-isomers, E- and Z-isomers, R- and S-enantiomers, diastereomers,(D)-isomers, (L)-isomers, the racemic mixtures thereof, and othermixtures thereof, as falling within the scope of the invention.Additional asymmetric carbon atoms may be present in a substituent suchas an alkyl group. All such isomers, as well as mixtures thereof, areintended to be included in this invention.

If, for instance, a particular enantiomer of compound of the presentinvention is desired, it may be prepared by asymmetric synthesis, or byderivation with a chiral auxiliary, where the resulting diastereomericmixture is separated and the auxiliary group cleaved to provide the puredesired enantiomers. Alternatively, where the molecule contains a basicfunctional group, such as amino, or an acidic functional group, such ascarboxyl, diastereomeric salts are formed with an appropriateoptically-active acid or base, followed by resolution of thediastereomers thus formed by fractional crystallization orchromatographic means well known in the art, and subsequent recovery ofthe pure enantiomers.

It will be understood that “substitution” or “substituted with” includesthe implicit proviso that such substitution is in accordance withpermitted valence of the substituted atom and the substituent, and thatthe substitution results in a stable compound, e.g., which does notspontaneously undergo transformation such as by rearrangement,cyclization, elimination, or other reaction.

The term “substituted” is also contemplated to include all permissiblesubstituents of organic compounds. In a broad aspect, the permissiblesubstituents include acyclic and cyclic, branched and unbranched,carbocyclic and heterocyclic, aromatic and nonaromatic substituents oforganic compounds. Illustrative substituents include, for example, thosedescribed herein above. The permissible substituents may be one or moreand the same or different for appropriate organic compounds. Forpurposes of this invention, the heteroatoms such as nitrogen may havehydrogen substituents and/or any permissible substituents of organiccompounds described herein which satisfy the valences of theheteroatoms. This invention is not intended to be limited in any mannerby the permissible substituents of organic compounds.

The phrase “protecting group” as used herein means temporarysubstituents which protect a potentially reactive functional group fromundesired chemical transformations. Examples of such protecting groupsinclude esters of carboxylic acids, silyl ethers of alcohols, andacetals and ketals of aldehydes and ketones, respectively. Examples ofnitrogen protecting groups include an amide (—NRC(═O)R) or a urethane(—NRC(═O)OR), for example, as: a methyl amide (—NHC(═O)CH₃); a benzyloxyamide (—NHC(═O)OCH₂C₆H₅; —NHCbz); as a t-butoxy amide (—NHC(═O)OC(CH₃)₃,—NHBoc); a 2-biphenyl-2-propoxy amide (—NHC(═O)OC(CH₃)₂C₆H₄C₆H₅), as a9-fluorenylmethoxy amide (—NHFmoc), as a 6-nitroveratryloxy amide(—NHNvoc), as a 2-trimethylsilylethyloxy amide (—NHTeoc), as a2,2,2-trichloroethyloxy amide (—NHTroc), as an allyloxy amide(—NHAlloc), as a 2-(phenylsulfonyl)ethyloxy amide (—NHPsec); or, insuitable cases (e.g., cyclic amines), as a nitroxide radical. The fieldof protecting group chemistry has been reviewed (Greene, T.W.; Wuts,P.G.M. Protective Groups in Organic Synthesis, 2^(nd) ed.; Wiley: NewYork, 1991). Protected forms of the inventive compounds are includedwithin the scope of this invention.

The term “pharmaceutically acceptable salt” or “salt” refers to a saltof one or more compounds. Suitable pharmaceutically acceptable salts ofcompounds include acid addition salts, such as those formed with mineralacids such as hydrochloric acid and hydrobromic acid, and also thoseformed with organic acids such as maleic acid. For example, acidscommonly employed to form pharmaceutically acceptable salts includeinorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic,hydroiodic, sulfuric and phosphoric acid, as well as organic acids suchas para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic,maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic,methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic,para-bromophenylsulfonic, carbonic, succinic, citric, benzoic and aceticacid, and related inorganic and organic acids. Such pharmaceuticallyacceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite,bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate,metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate,propionate, decanoate, caprylate, acrylate, formate, isobutyrate,caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate,sebacate, fumarate, maleate, butyne-1,4-dioate, hexyne-1,6-dioate,benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate,hydroxybenzoate, methoxybenzoate, phthalate, terephathalate, sulfonate,xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate,citrate, lactate, β-hydroxybutyrate, glycolate, maleate, tartrate,methanesulfonate, propanesulfonate, naphthalene-1-sulfonate,naphthalene-2-sulfonate, mandelate and the like.

Where the compounds carry one or more acidic moieties, pharmaceuticallyacceptable salts may be formed by treatment of a solution of thecompound with a solution of a pharmaceutically acceptable base. Suitablebases for forming pharmaceutically acceptable salts with acidicfunctional groups include, but are not limited to, hydroxides andcarbonates of alkali metals such as sodium, potassium, and lithium;alkaline earth metal such as calcium and magnesium; and other metals,such as aluminum and zinc. Suitable bases also include ammonia, andorganic amines, such as unsubstituted or hydroxy-substituted mono-, di-,or trialkylamines; dicyclohexylamine; tributyl amine; pyridine;N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, ortris-(2-hydroxy-lower alkyl amines), such as mono-, bis-, ortris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, ortris-(hydroxymethyl)methylamine, N,N-di alkyl-N-(hydroxy alkyl)-amines,such as N,N-dimethyl-N-(2-hydroxyethyl)amine, ortri-(2-hydroxyethyl)amine; N-methyl-D-glucamine; and amino acids such asarginine, lysine, and the like.

Certain compounds of the invention and their salts may exist in morethan one crystalline form (i.e., polymorph); the present inventionincludes each of the crystal forms and mixtures thereof.

Certain compounds of the invention and their salts may also exist in theform of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

Certain compounds of the invention may contain one or more chiralcenters, and exist in different optically active forms. When compoundsof the invention contain one chiral center, the compounds exist in twoenantiomeric forms and the present invention includes both enantiomersand mixtures of enantiomers, such as racemic mixtures thereof. Theenantiomers may be resolved by methods known to those skilled in theart; for example, enantiomers may be resolved by formation ofdiastereoisomeric salts which may be separated, for example, bycrystallization; formation of diastereoisomeric derivatives or complexeswhich may be separated, for example, by crystallization, gas-liquid orliquid chromatography; selective reaction of one enantiomer with anenantiomer-specific reagent, for example, via enzymatic esterification;or gas-liquid or liquid chromatography in a chiral environment, forexample, on a chiral support; suitable include chiral supports (e.g.,silica with a bound chiral ligand) or in the presence of a chiralsolvent. Where the desired enantiomer is converted into another chemicalentity by one of the separation procedures described above, a furtherstep may be used to liberate the desired purified enantiomer.Alternatively, specific enantiomers may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting one enantiomer into the other by asymmetrictransformation.

When a compound of the invention contains more than one chiral center,it may exist in diastereoisomeric forms. The diastereoisomeric compoundsmay be separated by methods known to those skilled in the art (forexample, chromatography or crystallization) and the individualenantiomers may be separated as described above. The present inventionincludes the various diastereoisomers of compounds of the invention, andmixtures thereof. Compounds of the invention may exist in differenttautomeric forms or as different geometric isomers, and the presentinvention includes each tautomer and/or geometric isomer of compounds ofthe invention, and mixtures thereof. For example, any olefins present inthe compounds may exist as either the E- or Z-geometric isomers or amixture thereof unless stated otherwise. Compounds of the invention mayexist in zwitterionic form. The present invention includes eachzwitterionic form of compounds of the invention, and mixtures thereof.

As used herein the term “pro-drug” refers to an agent, which isconverted into the parent drug in vivo by some physiological chemicalprocess (e.g., a prodrug on being brought to the physiological pH isconverted to the desired drug form). Pro-drugs are often useful because,in some situations, they may be easier to administer than the parentdrug. They may, for instance, be bioavailable by oral administrationwhereas the parent drug is not. The prodrug may also have improvedsolubility in pharmacological compositions over the parent drug. Anexample, without limitation, of a pro-drug would be a compound of thepresent invention wherein it is administered as an ester (the“pro-drug”) to facilitate transmittal across a cell membrane where watersolubility is not beneficial, but then it is metabolically hydrolyzed tothe carboxylic acid once inside the cell where water solubility isbeneficial. Pro-drugs have many useful properties. For example, apro-drug may be more water soluble than the ultimate drug, therebyfacilitating intravenous administration of the drug. A pro-drug may alsohave a higher level of oral bioavailability than the ultimate drug.After administration, the prodrug is enzymatically or chemically cleavedto deliver the ultimate drug in the blood or tissue.

Exemplary pro-drugs release an amine of a compound of the inventionwherein the free hydrogen of an amine or alcohol is replaced by—CH₂OP(═O)(OF)₂, —CH₂O(P═O)(OR₈)₂, —(C═O)OCHR₈O(C═O)CH₃, or—(C═O)OCH₂O(P═O)(OH)₂ (C₁-C₆)alkanoyloxymethyl,1-((C₁-C₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl,(C₁-C₆)alkoxycarbonyl-oxymethyl, N—(C₁-C₆)alkoxycarbonylamino-methyl,succinoyl, (C₁-C₆)alkanoyl, α-amino(C₁-C₄)alkanoyl, arylactyl andα-aminoacyl, or α-aminoacyl-α-aminoacyl wherein said α-aminoacylmoieties are independently any of the naturally occurring L-amino acidsfound in proteins, —P(O)(OH)₂, —P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (theradical resulting from detachment of the hydroxyl of the hemiacetal of acarbohydrate).

Other exemplary pro-drugs upon cleavage release a corresponding freeacid, and such hydrolyzable ester-forming residues of the compounds ofthis invention include but are not limited to carboxylic acidsubstituents (e.g., —(CH₂)C(O)OH or a moiety that contains a carboxylicacid) wherein the free hydrogen is replaced by (C₁-C₄)alkyl,(C₂-C₁₂)alkanoyloxymethyl, 1-((C₄-C₉)alkanoyloxy)ethyl,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N—(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)-alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl.

The term “subject” as used herein, refers to an animal, typically amammal or a human, that will be or has been the object of treatment,observation, and/or experiment. When the term is used in conjunctionwith administration of a compound or drug, then the subject has been theobject of treatment, observation, and/or administration of the compoundor drug.

The terms “co-administration” and “co-administering” refer to bothconcurrent administration (administration of two or more therapeuticagents at the same time) and time varied administration (administrationof one or more therapeutic agents at a time different from that of theadministration of an additional therapeutic agent or agents), as long asthe therapeutic agents are present in the patient to some extent at thesame time.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits abiological or medicinal response in a cell culture, tissue system,animal, or human that is being sought by a researcher, veterinarian,clinician, or physician, which includes alleviation of the symptoms ofthe disease, condition, or disorder being treated.

The term “composition” is intended to encompass a product comprising thespecified ingredients in the specified amounts, as well as any productthat results, directly or indirectly, from combinations of the specifiedingredients in the specified amounts.

The term “pharmaceutically acceptable carrier” refers to a medium thatis used to prepare a desired dosage form of a compound. Apharmaceutically acceptable carrier can include one or more solvents,diluents, or other liquid vehicles; dispersion or suspension aids;surface active agents; isotonic agents; thickening or emulsifyingagents; preservatives; solid binders; lubricants; and the like.Remington's Pharmaceutical Sciences, Fifteenth Edition, E. W. Martin(Mack Publishing Co., Easton, Pa., 1975) and Handbook of PharmaceuticalExcipients, Third Edition, A. H. Kibbe ed. (American PharmaceuticalAssoc. 2000), disclose various carriers used in formulatingpharmaceutical compositions and known techniques for the preparationthereof.

Exemplary Compounds

An aspect of the present invention relates to compounds that inhibitcasein kinase 1 and/or casein kinase 2 and/or a PIM kinase. For example,an embodiment relates to a compound of formula 1 or a pharmaceuticallyacceptable salt thereof:

wherein independently for each occurrence

-   -   X is —N(R₇)₂, —N(R₇)(R₂), or —N(H)—R₃-R₆;    -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;    -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,        —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;    -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;    -   R₅ is selected from the group consisting of 1,4-cyclohexanediyl,        1,4-phenylene, 1,4-cycloheptanediyl, 1,4-cyclooctanediyl,        1,5-cyclooctanediyl, 1,4-bicyclo[2.2.1]heptanediyl,        1,4-bicyclo[2.2.2]octanediyl, and 1,5-bicyclo[3.3.1]nonanediyl;    -   R₆ is selected from the group consisting of alkyl, alkylaryl,        aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of        which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of alkyl, alkylaryl, aralkyl (including but not        limited to benzyl), aryl (including but not limited to phenyl),        heteroaryl (including but not limited to pyridyl, imidazolyl,        thiazolyl, furyl, and thionyl), alkoxy (including but not        limited to methoxy), hydroxy, perfluoroalkyl (including but not        limited to trifluoromethyl), trifluoromethoxy, and halide        (including but not limited to fluoride and chloride), wherein        the optional aryl or heteroaryl substituent may be optionally        substituted with alkyl, halide, alkoxy, perfluoroalkyl, or        dioxolanyl;    -   R₇ is selected from the group consisting of H, —C(═NR)R,        —(C(R)₂)_(n)R, alkyl, alkylaryl, aryl, alkylheteroaryl,        alkylheteroalkyl, and heteroaryl, any of which is optionally        mono or di-substituted, and the substituents, if present, are        independently selected from the group consisting of alkyl,        alkylaryl, aralkyl, aryl, heteroaryl, alkoxy, hydroxy,        perfluoroalkyl, trifluoromethoxy, and halide, wherein the        optional aryl or heteroaryl substituent may be optionally        substituted with alkyl, halide, alkoxy, perfluoroalkyl, or        dioxolanyl, or    -   two instances of R₇ and the nitrogen to which they are bonded        taken together represent a nitrogen-containing heterocyclyl,        optionally containing one additional heteroatom in the ring,        wherein said additional heteroatom is selected from the group        consisting of —O—, —N(R)—, and —S—;    -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl;    -   R is H or (C₁-C₄)alkyl; and    -   n is 1, 2 or 3.

In one embodiment, R′ is H.

In one embodiment, R′ is methyl.

In one embodiment, R′ is (C₂-C₄)alkyl.

In one embodiment, R′ is benzyl.

In one embodiment, R₂ is H.

In one embodiment, R₂ is —CH₂OP(═O)(OH)₂.

In one embodiment, R₅ is 1,4-cyclohexanediyl.

In one embodiment, R₅ is 1,4-phenylene.

In one embodiment, R₆ is selected from the group consisting of alkyl,aryl, and heteroaryl.

In one embodiment, R₆ is selected from the group consisting of phenyl,biphenyl, pyridyl, pyrimidyl, naphthyl, quinolinyl, furanyl, andthienyl.

In one embodiment, R₆ is phenyl; the substituents are independentlyselected from the group consisting of alkyl, aryl, heteroaryl, alkoxy,perfluoroalkyl, halide; and the aryl or heteroaryl substituent issubstituted with a substituent selected from the group consisting ofalkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is phenyl; the substituents are independentlyselected from the group consisting of phenyl, methoxy, trifluoromethyl,trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl,furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl,furyl, or thienyl substituent is substituted with a substituent selectedfrom the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, anddioxolanyl.

In one embodiment, R₆ is pyridyl; the substituents are independentlyselected from the group consisting of alkyl, aryl, heteroaryl, alkoxy,perfluoroalkyl, halide; and the aryl or heteroaryl substituent issubstituted with a substituent selected from the group consisting ofalkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyridyl; the substituents are independentlyselected from the group consisting of phenyl, methoxy, trifluoromethyl,trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl,furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl,furyl, or thienyl substituent is substituted with a substituent selectedfrom the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, anddioxolanyl.

In one embodiment, R₆ is pyrimidyl; the substituents are independentlyselected from the group consisting of alkyl, aryl, heteroaryl, alkoxy,perfluoroalkyl, halide; and the aryl or heteroaryl substituent issubstituted with a substituent selected from the group consisting ofalkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyrimidyl; the substituents are independentlyselected from the group consisting of phenyl, methoxy, trifluoromethyl,trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl,furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl,furyl, or thienyl substituent is substituted with a substituent selectedfrom the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, anddioxolanyl.

In one embodiment, R₆ is naphthyl; the substituents are independentlyselected from the group consisting of alkyl, aryl, heteroaryl, alkoxy,perfluoroalkyl, halide; and the aryl or heteroaryl substituent issubstituted with a substituent selected from the group consisting ofalkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is naphthyl; the substituents are independentlyselected from the group consisting of phenyl, methoxy, trifluoromethyl,trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl,furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl,furyl, or thienyl substituent is substituted with a substituent selectedfrom the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, anddioxolanyl.

In one embodiment, R₆ is naphthyl; and the substituent is fluoride.

In one embodiment, R₆ is quinolinyl; the substituents are independentlyselected from the group consisting of alkyl, aryl, heteroaryl, alkoxy,perfluoroalkyl, halide; and the aryl or heteroaryl substituent issubstituted with a substituent selected from the group consisting ofalkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is quinolinyl; the substituents are independentlyselected from the group consisting of phenyl, methoxy, trifluoromethyl,trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl,furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl,furyl, or thienyl substituent is substituted with a substituent selectedfrom the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, anddioxolanyl.

In one embodiment, R₆ is quinolinyl; and the substituent is methyl.

In one embodiment, R₈ is H.

One aspect of the invention is a compound of formula 2 or apharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   X is —N(R₇)₂, —N(R₇)(R₂), or —N(H)—R₃-R₄;    -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;    -   R₁ is selected from the group consisting of 1,4-cyclohexanediyl        and 1,4-phenylene;    -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂, (C═O)OCHR₈O(C═O)CH₃,        or —(C═O)OCH₂O(P═O)(OH)₂;    -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;    -   R₄ is selected from the group consisting of aryl and heteroaryl,        either of which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of halide, alkyl, perfluoroalkyl, aryl,        heteroaryl, and heterocyclyl; wherein the optional aryl or        heteroaryl substituent is itself optionally substituted with        perfluoroalkyl or dioxolane;    -   R₇ is selected from the group consisting of H, —C(═NR)R,        —(C(R)₂)_(n)R, alkyl, alkylaryl, aryl, alkylheteroaryl,        alkylheteroalkyl, and heteroaryl, any of which is optionally        mono or di-substituted, and the substituents, if present, are        independently selected from the group consisting of alkyl,        alkylaryl, aralkyl (including but not limited to benzyl), aryl        (including but not limited to phenyl), heteroaryl (including but        not limited to pyridyl, imidazolyl, thiazolyl, furyl, and        thionyl), alkoxy (including but not limited to methoxy),        hydroxy, perfluoroalkyl (including but not limited to        trifluoromethyl), trifluoromethoxy, and halide (including but        not limited to fluoride and chloride), wherein the optional aryl        or heteroaryl substituent may be optionally substituted with        alkyl, halide, alkoxy, perfluoroalkyl, or dioxolanyl, or    -   two instances of R₇ and the nitrogen to which they are bonded        taken together represent a nitrogen-containing heterocyclyl,        optionally containing one additional heteroatom in the ring,        wherein said additional heteroatom is selected from the group        consisting of —O—, —N(R)—, and —S—;    -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl;    -   R is H or (C₁-C₄)alkyl; and    -   n is 1, 2 or 3.

In one embodiment, R′ is H.

In one embodiment, R′ is methyl.

In one embodiment, R′ is (C₂-C₄)alkyl.

In one embodiment, R′ is benzyl.

In one embodiment, R₁ is 1,4-cyclohexanediyl.

In one embodiment, R₁ is 1,4-phenylene.

In one embodiment, R₄ is selected from the group consisting of phenyl,pyridyl, naphthyl, quinolinyl, furanyl, and thienyl.

In one embodiment, R₄ is phenyl, and the substituents are independentlyselected from the group consisting of fluoride, furyl, and thienyl.

In one embodiment, R₄ is pyridyl, and the substituents are independentlyselected from the group consisting of halide, aryl, heteroaryl, andheterocyclyl; wherein the aryl and heteroaryl are optionally substitutedwith perfluoroalkyl or dioxolane.

In one embodiment, R₄ is pyridyl, and the substituents are independentlyselected from the group consisting fluoride, furyl, thienyl,trifluormethylphenyl, trifluoromethylthienyl, and 1,3 benzodioxozole.

In one embodiment, R₄ is naphthyl, and the substituent is fluoride.

In one embodiment, R₄ is quinolinyl, and the substituent is methyl.

In one embodiment, the invention relates to any one of theaforementioned compounds, wherein X is —N(R₇)₂, and —N(R₇)₂ represents

In one embodiment, the invention relates to any one of theaforementioned compounds, wherein R₃ is selected from the groupconsisting of —CH₂—, —CH(CH₃)—, —CH₂CH₂—, —CH₂CH₂CH₂—, and —C(═NH)—.

Another embodiment relates to a compound of formula 3 or apharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,        —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;    -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;    -   R is H or (C₁-C₄)alkyl;    -   n is 1, 2 or 3;    -   R₆ is selected from the group consisting of alkyl, alkylaryl,        aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of        which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of alkyl, alkylaryl, aralkyl (including but not        limited to benzyl), aryl (including but not limited to phenyl),        heteroaryl (including but not limited to pyridyl, imidazolyl,        thiazolyl, furyl, and thionyl), alkoxy (including but not        limited to methoxy), hydroxy, perfluoroalkyl (including but not        limited to trifluoromethyl), trifluoromethoxy, and halide        (including but not limited to fluoride and chloride), wherein        the optional aryl or heteroaryl substituent may be optionally        substituted with alkyl, halide, alkoxy, perfluoroalkyl, or        dioxolanyl; and    -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

In one embodiment, R₂ is H.

In one embodiment, R₂ is —CH₂OP(═O)(OH)₂.

In one embodiment, R₃ is —CH₂—.

In one embodiment, R₆ is selected from the group consisting of alkyl,aryl, and heteroaryl.

In one embodiment, R₆ is selected from the group consisting of phenyl,biphenyl, pyridyl, pyrimidyl, naphthyl, quinolinyl, furanyl, andthienyl.

In one embodiment, R₆ is phenyl; the substituents are independentlyselected from the group consisting of alkyl, aryl, heteroaryl, alkoxy,perfluoroalkyl, halide; and the aryl or heteroaryl substituent issubstituted with a substituent selected from the group consisting ofalkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is phenyl; the substituents are independentlyselected from the group consisting of phenyl, methoxy, trifluoromethyl,trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl,furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl,furyl, or thienyl substituent is substituted with a substituent selectedfrom the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, anddioxolanyl.

In one embodiment, R₆ is pyridyl; the substituents are independentlyselected from the group consisting of alkyl, aryl, heteroaryl, alkoxy,perfluoroalkyl, halide; and the aryl or heteroaryl substituent issubstituted with a substituent selected from the group consisting ofalkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyridyl; the substituents are independentlyselected from the group consisting of phenyl, methoxy, trifluoromethyl,trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl,furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl,furyl, or thienyl substituent is substituted with a substituent selectedfrom the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, anddioxolanyl.

In one embodiment, R₆ is pyrimidyl; the substituents are independentlyselected from the group consisting of alkyl, aryl, heteroaryl, alkoxy,perfluoroalkyl, halide; and the aryl or heteroaryl substituent issubstituted with a substituent selected from the group consisting ofalkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is pyrimidyl; the substituents are independentlyselected from the group consisting of phenyl, methoxy, trifluoromethyl,trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl,furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl,furyl, or thienyl substituent is substituted with a substituent selectedfrom the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, anddioxolanyl.

In one embodiment, R₆ is naphthyl; the substituents are independentlyselected from the group consisting of alkyl, aryl, heteroaryl, alkoxy,perfluoroalkyl, halide; and the aryl or heteroaryl substituent issubstituted with a substituent selected from the group consisting ofalkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is naphthyl; the substituents are independentlyselected from the group consisting of phenyl, methoxy, trifluoromethyl,trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl,furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl,furyl, or thienyl substituent is substituted with a substituent selectedfrom the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, anddioxolanyl.

In one embodiment, R₆ is naphthyl; and the substituent is fluoride.

In one embodiment, R₆ is quinolinyl; the substituents are independentlyselected from the group consisting of alkyl, aryl, heteroaryl, alkoxy,perfluoroalkyl, halide; and the aryl or heteroaryl substituent issubstituted with a substituent selected from the group consisting ofalkyl, halide, alkoxy, perfluoroalkyl, and dioxolanyl.

In one embodiment, R₆ is quinolinyl; the substituents are independentlyselected from the group consisting of phenyl, methoxy, trifluoromethyl,trifluoromethoxy, fluoride, chloride, pyridyl, imidazolyl, thiazolyl,furyl, and thienyl; and the phenyl, pyridyl, imidazolyl, thiazolyl,furyl, or thienyl substituent is substituted with a substituent selectedfrom the group consisting of alkyl, halide, alkoxy, perfluoroalkyl, anddioxolanyl.

In one embodiment, R₆ is quinolinyl; and the substituent is methyl.

In one embodiment, R₈ is H.

Another embodiment relates to a compound of formula 4 or apharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;    -   R is H or (C₁-C₄)alkyl;    -   n is 1, 2 or 3; and    -   R₄ is selected from the group consisting of aryl and heteroaryl,        either of which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of halide, alkyl, perfluoroalkyl, aryl,        heteroaryl, and heterocyclyl; wherein the optional aryl or        heteroaryl substituent is itself optionally substituted with        perfluoroalkyl or dioxolane.

In one embodiment, R₄ is selected from the group consisting of phenyl,pyridyl, naphthyl, quinolinyl, furanyl, and thienyl.

In one embodiment, R₄ is phenyl, and the substituents are independentlyselected from the group consisting of fluoride, furyl, and thienyl.

In one embodiment, R₄ is pyridyl, and the substituents are independentlyselected from the group consisting of halide, aryl, heteroaryl, andheterocyclyl; wherein the aryl and heteroaryl are optionally substitutedwith perfluoroalkyl or dioxolane.

In one embodiment, R₄ is pyridyl, and the substituents are independentlyselected from the group consisting fluoride, furyl, thienyl,trifluormethylphenyl, trifluoromethylthienyl, and 1,3 benzodioxozole.

In one embodiment, R₄ is naphthyl, and the substituent is fluoride.

In one embodiment, R₄ is quinolinyl, and the substituent is methyl.

In one embodiment, R₃ is selected from the group consisting of —CH₂—,—CH(CH₃)—, —CH₂CH₂—, —CH₂CH₂CH₂—, and —C(═NH)—.

Another embodiment relates to a compound of formula 5 or apharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;    -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,        —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;    -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;    -   R is H or (C₁-C₄)alkyl;    -   n is 1, 2 or 3;    -   R₆ is selected from the group consisting of alkyl, alkylaryl,        aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of        which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of alkyl, alkylaryl, aralkyl (including but not        limited to benzyl), aryl (including but not limited to phenyl),        heteroaryl (including but not limited to pyridyl, imidazolyl,        thiazolyl, furyl, and thionyl), alkoxy (including but not        limited to methoxy), hydroxy, perfluoroalkyl (including but not        limited to trifluoromethyl), trifluoromethoxy, and halide        (including but not limited to fluoride and chloride), wherein        the optional aryl or heteroaryl substituent may be optionally        substituted with alkyl, halide, alkoxy, perfluoroalkyl, or        dioxolanyl; and    -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

In one embodiment, R′ is H.

In one embodiment, R′ is methyl.

In one embodiment, R′ is (C₂-C₄)alkyl.

In one embodiment, R′ is benzyl.

In one embodiment, R₂ is H.

In one embodiment, R₂ is —CH₂OP(═O)(OH)₂.

Another embodiment relates to a compound of formula 6 or apharmaceutically acceptable salt thereof:

wherein independently for each occurrence

-   -   R′ is H, methyl, (C₂-C₄)alkyl, or benzyl;    -   R₂ is H, —CH₂OP(═O)(OH)₂, —CH₂O(P═O)(OR₈)₂,        —(C═O)OCHR₈O(C═O)CH₃, or —(C═O)OCH₂O(P═O)(OH)₂;    -   R₃ is —C(═NR)— or —(C(R)₂)_(n)—;    -   R is H or (C₁-C₄)alkyl;    -   n is 1, 2 or 3;    -   R₆ is selected from the group consisting of alkyl, alkylaryl,        aryl, alkylheteroaryl, alkylheteroalkyl, and heteroaryl, any of        which is optionally mono or di-substituted, and the        substituents, if present, are independently selected from the        group consisting of alkyl, alkylaryl, aralkyl (including but not        limited to benzyl), aryl (including but not limited to phenyl),        heteroaryl (including but not limited to pyridyl, imidazolyl,        thiazolyl, furyl, and thionyl), alkoxy (including but not        limited to methoxy), hydroxy, perfluoroalkyl (including but not        limited to trifluoromethyl), trifluoromethoxy, and halide        (including but not limited to fluoride and chloride), wherein        the optional aryl or heteroaryl substituent may be optionally        substituted with alkyl, halide, alkoxy, perfluoroalkyl, or        dioxolanyl; and    -   R₈ is H, alkyl, benzyl, t-butyl, aryl, or heteroaryl.

In one embodiment, R′ is H.

In one embodiment, R′ is methyl.

In one embodiment, R′ is (C₂-C₄)alkyl.

In one embodiment, R′ is benzyl.

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

In one embodiment, the compound is selected from the group consistingof:

Any one of the aforementioned compounds may exist as the E-geometricisomer, the Z-geometric isomer, or mixtures thereof. For example, in oneembodiment,

in the aforementioned structures represents the E-isomer of theparticular compound. In another embodiment,

represents the Z-isomer of the particular compound. In yet anotherembodiment,

represents a mixture of E and Z isomers of the particular compound.

In one embodiment, any one of the aforementioned compounds is aninhibitor of CK1, CK1γ1, CK1γ2, or CK1γ3.

In one embodiment, any one of the aforementioned compounds is aninhibitor of CK2.

In one embodiment, any one of the aforementioned compounds is aninhibitor of the Wnt pathway.

In one embodiment, any one of the aforementioned compounds is aninhibitor of the JAK/STAT pathway.

In one embodiment, any one of the aforementioned compounds is aninhibitor of the mTOR pathway.

In one embodiment, any one of the aforementioned compounds is aninhibitor of the AKT pathway.

In one embodiment, any one of the aforementioned compounds is a mediatorof Pgp degradation and/or drug efflux.

In one embodiment, any one of the aforementioned compounds is aninhibitor of the TGFβ pathway.

In some embodiments, the compound has an IC₅₀ of less than about 5000 nMfor CK1, CK1γ1, CK1γ2, or CK1γ3.

In some embodiments, the compound has an IC₅₀ of less than about 1000 nMfor CK1, CK1γ1, CK1γ2, or CK1γ3.

In some embodiments, the compound has an IC₅₀ of less than about 500 nMfor CK1, CK1γ1, CK1γ2, or CK1γ3.

In one embodiment, any one of the aforementioned compounds is aninhibitor of CK2.

In one embodiment, the compound has an IC₅₀ of less than about 5000 nMfor CK2.

In one embodiment, the compound has an IC₅₀ of less than about 1000 nMfor CK2.

In one embodiment, the compound has an IC₅₀ of less than about 500 nMfor CK2.

In one embodiment, any one of the aforementioned compounds is aninhibitor of PIM1, PIM2, or PIM3.

In one embodiment, the compound has an IC₅₀ of less than about 5000 nMfor PIM1, PIM2 or PIM3.

In one embodiment, the compound has an IC₅₀ of less than about 1000 nMfor PIM1, PIM2 or PIM3.

In one embodiment, the compound has an IC₅₀ of less than about 500 nMfor PIM1, PIM2 or PIM3.

In addition, it may be convenient or desirable to prepare, purify,and/or handle the active compound in a chemically protected form. Theterm “chemically protected form,” as used herein, pertains to a compoundin which one or more reactive functional groups are protected fromundesirable chemical reactions (i.e., they have been modified with aprotecting group).

By protecting a reactive functional group, reactions involving otherunprotected reactive functional groups can be performed withoutaffecting the protected group; the protecting group may be removed,usually in a subsequent step, without substantially affecting theremainder of the molecule. See, for example, Protective Groups inOrganic Synthesis (T. Green and P. Wuts, Wiley, 1991), and ProtectiveGroups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; JohnWiley and Sons, 1999).

For example, a hydroxy group may be protected as an ether (—OR) or anester (—OC(═O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl(diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl ort-butyldimethylsilyl ether; or an acetyl ester (—OC(═O)CH₃, —OAc).

For example, an aldehyde or ketone group may be protected as an acetalor ketal, respectively, in which the carbonyl group (C(═O)) is convertedto a diether (C(OR)₂), by reaction with, for example, a primary alcohol.The aldehyde or ketone group is readily regenerated by hydrolysis usinga large excess of water in the presence of acid.

For example, an amine group may be protected, for example, as an amide(—NRC(═O)R) or a urethane (—NRC(═O)OR), for example, as: a methyl amide(—NHC(═O)CH₃); a benzyloxy amide (—NHC(═O)OCH₂C₆H₅; —NHCbz); as at-butoxy amide (—NHC(═O)OC(CH₃)₃, —NHBoc); a 2-biphenyl-2-propoxy amide(—NHC(═O)OC(CH₃)₂C₆H₄C₆H₅), as a 9-fluorenylmethoxy amide (—NHFmoc), asa 6-nitroveratryloxy amide (—NHNvoc), as a 2-trimethylsilylethyloxyamide (—NHTeoc), as a 2,2,2-trichloroethyloxy amide (—NHTroc), as anallyloxy amide (—NHAlloc), as a 2-(phenylsulfonyl)ethyloxy amide(—NHPsec); or, in suitable cases (e.g., cyclic amines), as a nitroxideradical.

For example, a carboxylic acid group may be protected as an ester or anamide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester;or a methyl amide.

For example, a thiol group may be protected as a thioether (—SR), forexample, as: a benzyl thioether; or an acetamidomethyl ether(—SCH₂NHC(═O)CH₃).

Exemplary Pharmaceutical Compositions

One or more compounds of this invention can be administered to a mammalby themselves or in pharmaceutical compositions where they are mixedwith suitable carriers or excipient(s) at doses to treat or ameliorate adisease or condition as described herein. Mixtures of these compoundscan also be administered to the patient as a simple mixture or insuitable formulated pharmaceutical compositions. For example, one aspectof the invention relates to pharmaceutical composition comprising atherapeutically effective dose of a compound of formula 1, 2, 3, 4, 5,or 6, or a pharmaceutically acceptable salt, solvate, enantiomer orstereoisomer thereof; and a pharmaceutically acceptable diluent orcarrier.

Techniques for formulation and administration of the compounds of theinstant application may be found in references well known to one ofordinary skill in the art, such as “Remington's PharmaceuticalSciences,” Mack Publishing Co., Easton, Pa., latest edition.

Suitable routes of administration may, for example, include oral,eyedrop, rectal, transmucosal, topical, or intestinal administration;parenteral delivery, including intramuscular, subcutaneous,intramedullary injections, as well as intrathecal, directintraventricular, intravenous, intraperitoneal, intranasal, orintraocular injections.

Alternatively, one may administer a compound in a local rather than asystemic manner, for example, via injection of the compound directlyinto an oedematous site, often in a depot or sustained releaseformulation.

Furthermore, one may administer a compound in a targeted drug deliverysystem, for example, in a liposome coated with endothelial-cell-specificantibody.

The pharmaceutical compositions of the present invention may bemanufactured, e.g., by means of conventional mixing, dissolving,granulating, dragee-making, levigating, emulsifying, encapsulating,entrapping or lyophilizing processes.

Pharmaceutical compositions for use in accordance with the presentinvention thus may be formulated in a conventional manner using one ormore physiologically acceptable carriers comprising excipients andauxiliaries which facilitate processing of the active compounds intopreparations which can be used pharmaceutically. Proper formulation isdependent upon the route of administration chosen.

For injection, the agents of the invention may be formulated in aqueoussolutions, preferably in physiologically compatible buffers such asHanks' solution, Ringer's solution, or physiological saline buffer. Fortransmucosal administration, penetrants are used in the formulationappropriate to the barrier to be permeated. Such penetrants aregenerally known in the art.

For oral administration, the compounds can be formulated readily bycombining the active compounds with pharmaceutically acceptable carrierswell known in the art. Such carriers enable the compounds of theinvention to be formulated as tablets, pills, dragees, capsules,liquids, gels, syrups, slurries, suspensions and the like, for oralingestion by a patient to be treated. Pharmaceutical preparations fororal use can be obtained by combining the active compound with a solidexcipient, optionally grinding a resulting mixture, and processing themixture of granules, after adding suitable auxiliaries, if desired, toobtain tablets or dragee cores. Suitable excipients include fillers suchas sugars, including lactose, sucrose, mannitol, or sorbitol; cellulosepreparations such as, for example, maize starch, wheat starch, ricestarch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/orpolyvinylpyrrolidone (PVP). If desired, disintegrating agents may beadded, such as the cross-linked polyvinyl pyrrolidone, agar, or alginicacid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

Pharmaceutical preparations which can be used orally include push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules can contain the active ingredients in admixture with fillersuch as lactose, binders such as starches, and/or lubricants such astalc or magnesium stearate and, optionally, stabilizers. In softcapsules, the active compounds may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols. In addition, stabilizers may be added.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to thepresent invention are conveniently delivered in the form of an aerosolspray presentation from pressurized packs or a nebuliser, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of pressurized aerosol the dosage unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

The compounds can be formulated for parenteral administration byinjection, e.g., bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents.

Pharmaceutical formulations for parenteral administration includeaqueous solutions of the active compounds in water-soluble form.Additionally, suspensions of the active compounds may be prepared asappropriate oily injection suspensions. Suitable lipophilic solvents orvehicles include fatty oils such as sesame oil, or synthetic fatty acidesters, such as ethyl oleate or triglycerides, or liposomes. Aqueousinjection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form forreconstitution before use with a suitable vehicle, e.g., sterilepyrogen-free water.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter or other glycerides.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example, subcutaneously orintramuscularly or by intramuscular injection). Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives (for example, as asparingly soluble salt).

Alternatively, other delivery systems for hydrophobic pharmaceuticalcompounds may be employed. Liposomes and emulsions are examples ofdelivery vehicles or carriers for hydrophobic drugs. Certain organicsolvents such as dimethysulfoxide also may be employed. Additionally,the compounds may be delivered using a sustained-release system, such assemi-permeable matrices of solid hydrophobic polymers containing thetherapeutic agent. Various sustained-release materials have beenestablished and are well known by those skilled in the art.Sustained-release capsules may, depending on their chemical nature,release the compounds for a few weeks up to over 100 days. Depending onthe chemical nature and the biological stability of the therapeuticreagent, additional strategies for protein stabilization may beemployed.

The pharmaceutical compositions may also comprise suitable solid or gelphase carriers or excipients. Examples of such carriers or excipientsinclude but are not limited to calcium carbonate, calcium phosphate,various sugars, starches, cellulose derivatives, gelatin, and polymers,such as polyethylene glycols.

Exemplary Methods of Treatment

Provided herein are methods of modulating the activity of CK1 andsubtypes thereof, CK2, the Wnt pathway, and/or the TGFβ pathway. Alsoprovided herein are methods of treating or preventing conditions anddiseases the course of which can be influenced by modulating theactivity of CK1 (e.g., CK1γ), CK2, the Wnt pathway, and/or the TGFβpathway. Such methods typically comprise administering to a subject inneed thereof a therapeutically effective amount of a compound orcomposition of the invention.

Also provided herein are methods of modulating the activity of PIM, suchas PIM 1, PIM 2 or PIM 3, the JAK/STAT pathway, the AKT pathway, and/orthe mTOR pathway, and/or Pgp. Also provided herein are methods oftreating or preventing conditions and diseases, the course of which canbe influenced by modulating the activity of the PIMs, the JAK/STATpathway, the AKT pathway, and/or the mTOR pathway, and/or Pgp. Suchmethods typically comprise administering to a subject in need thereof atherapeutically effective amount of a compound or composition of theinvention.

Various diseases, such as cancers, inflammation, and inflammatorydiseases (e.g., osteoarthritis and rheumatoid arthritis), andneurological conditions (e.g., Alzheimer's disease) andneurodegeneration can be treated by administration of modulators of CK1(e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβ pathway. Bone-relateddiseases and conditions, including osteoporosis and bone formation, alsocan be treated by administration of modulators of CK1 (e.g., CK1γ), CK2,the Wnt pathway and/or the TGFβ pathway. Bone restoration can befacilitated by administration of modulators of CK1 (e.g., CK1γ), CK2,the Wnt pathway and/or the TGFβ pathway. Additional conditions that canbe treated by administration of modulators of CK1 (e.g., CK1γ), CK2, theWnt pathway and/or the TGFβ pathway include hypoglycemia, metabolicsyndrome and diabetes. Modulators of CK1 (e.g., CK1γ), CK2, the Wntpathway and/or the TGFβ pathway are also useful for influencingapoptosis (e.g., increasing the rate of apoptosis in cancerous cells).Modulators of CK1 (e.g., CK1γ), CK2, the Wnt pathway and/or the TGFβpathway are also useful in treatment or prevention of aberrant embryonicdevelopment.

Based at least on the fact that increased CK1γ has been found to beassociated with certain cancers, a method for treating cancer in asubject comprises administering to the subject in need thereof atherapeutically effective amount of a compound that inhibits CK1γ. PIM1,PIM2, PIM3, the JAK/STAT pathway, the AKT pathway, and/or the mTORpathway have also been found to be associated with certain cancers.Therefore, provided herein is a method for treating cancer comprisingadministering to a subject in need thereof a therapeutically effectiveamount of a compound that inhibits PIM1 and/or PIM2 and/or PIM3.

PIM1, PIM2, and PIM3 have also been associated with protecting Pgp fromdegradation, which can regulate drug efflux and drug resistance.Therefore, provided herein is a method for treating malignanciescomprising administering to a subject in need thereof a therapeuticallyeffective amount of a compound that inhibits PIM1 and/or PIM2 and/orPIM3 in conjunction with another drug, compound or material to abrogateresistance to the drug, compound or material.

The compounds described herein can be used for modulating cellproliferation, generally. Accordingly, diseases that may be treatedinclude hyperproliferative diseases, such as benign cell growth andmalignant cell growth.

Exemplary cancers that may be treated include leukemias, e.g., acutelymphoid leukemia and myeloid leukemia, and carcinomas, such ascolorectal carcinoma and hepatocarcinoma. Other cancers include AcuteLymphoblastic Leukemia; Acute Myeloid Leukemia; Adrenocortical CarcinomaAdrenocortical Carcinoma; AIDS-Related Cancers; AIDS-Related Lymphoma;Anal Cancer; Astrocytoma, Childhood Cerebellar; Astrocytoma, ChildhoodCerebral; Basal Cell Carcinoma, see Skin Cancer (non-Melanoma); BileDuct Cancer, Extrahepatic; Bladder Cancer; Bone Cancer,osteosarcoma/Malignant Fibrous Histiocytoma; Brain Stem Glioma; BrainTumor; Brain Tumor, Brain Stem Glioma; Brain Tumor, CerebellarAstrocytoma; Brain Tumor, Cerebral Astrocytoma/Malignant Glioma; BrainTumor, Ependymoma; Brain Tumor, Medulloblastoma; Brain Tumor,Supratentorial Primitive Neuroectodermal Tumors; Brain Tumor, VisualPathway and Hypothalamic Glioma; Brain Tumor; Breast Cancer; BreastCancer and Pregnancy; Breast Cancer; Breast Cancer, Male; BronchialAdenomas/Carcinoids; Burkitt's Lymphoma; Carcinoid Tumor; CarcinoidTumor, Gastrointestinal; Carcinoma of Unknown Primary; Central NervousSystem Lymphoma, Primary; Cerebellar Astrocytoma; CerebralAstrocytoma/Malignant Glioma; Cervical Cancer; Childhood Cancers;Chronic Lymphocytic Leukemia; Chronic Myelogenous Leukemia; ChronicMyeloproliferative Disorders; Colon Cancer; Colorectal Cancer; CutaneousT-Cell Lymphoma, see Mycosis Fungoides and Sezary Syndrome; EndometrialCancer; Ependymoma; Esophageal Cancer; Ewing's Family of Tumors;Extracranial Germ Cell Tumor; Extragonadal Germ Cell Tumor; ExtrahepaticBile Duct Cancer; Eye Cancer, Intraocular Melanoma; Eye Cancer,Retinoblastoma; Gallbladder Cancer; Gastric (Stomach) Cancer;Gastrointestinal Carcinoid Tumor; Germ Cell Tumor, Extracranial; GermCell Tumor, Extragonadal; Germ Cell Tumor, Ovarian; GestationalTrophoblastic Tumor; Glioma; Glioma, Childhood Brain Stem; Glioma,Childhood Cerebral Astrocytoma; Glioma, Childhood Visual Pathway andHypothalamic; Hairy Cell Leukemia; Head and Neck Cancer; Hematologic(Blood) Cancer, Hepatocellular (Liver) Cancer, Adult (Primary);Hepatocellular (Liver) Cancer, Childhood (Primary); Hodgkin's Lymphoma;Hodgkin's Lymphoma During Pregnancy; Hypopharyngeal Cancer; Hypothalamicand Visual Pathway Glioma; Intraocular Melanoma; Islet Cell Carcinoma(Endocrine Pancreas); Kaposi's Sarcoma; Kidney (Renal Cell) Cancer;Kidney Cancer; Laryngeal Cancer; Leukemia, Acute Lymphoblastic;Leukemia, Acute Lymphoblastic; Leukemia, Acute Myeloid; Leukemia, AcuteMyeloid; Leukemia, Chronic Lymphocytic; Leukemia, Chronic Myelogenous;Leukemia, Hairy Cell; Lip and Oral Cavity Cancer; Liver Cancer, Adult(Primary); Liver Cancer, Childhood (Primary); Lung Cancer, Non-SmallCell; Lung Cancer, Small Cell; Lymphoma, AIDS-Related; Lymphoma,Burkitt's; Lymphoma, Cutaneous T-Cell, see Mycosis Fungoides and SezarySyndrome; Lymphoma, Hodgkin's; Lymphoma, Hodgkin's During Pregnancy;Lymphoma, Non-Hodgkin's; Lymphoma, Non-Hodgkin's During Pregnancy;Lymphoma, Primary Central Nervous System; Macroglobulinemia,Waldenstrom's; Malignant Fibrous Histiocytoma of Bone/Osteosarcoma;Medulloblastoma; Melanoma; Melanoma, Intraocular (Eye); Merkel CellCarcinoma; Mesothelioma, Adult Malignant; Mesothelioma; MetastaticSquamous Neck Cancer with Occult Primary; Multiple Endocrine NeoplasiaSyndrome; Multiple Myeloma/Plasma Cell Neoplasm; Mycosis Fungoides;Myelodysplastic Syndromes; Myelodysplastic/Myeloproliferative Diseases;Myelogenous Leukemia, Chronic; Myeloid Leukemia, Adult Acute; MyeloidLeukemia, Childhood Acute; Myeloma, Multiple; MyeloproliferativeDisorders, Chronic; Nasal Cavity and Paranasal Sinus Cancer;Nasopharyngeal Cancer; Neuroblastoma; Non-Hodgkin's Lymphoma;Non-Hodgkin's Lymphoma During Pregnancy; Non-Small Cell Lung Cancer;Oral Cancer; Oral Cavity Cancer, Lip and; Oropharyngeal Cancer;Osteosarcoma/Malignant Fibrous Histiocytoma of Bone; Ovarian Cancer;Ovarian Epithelial Cancer; Ovarian Germ Cell Tumor; Ovarian LowMalignant Potential Tumor; Pancreatic Cancer, Islet Cell; ParanasalSinus and Nasal Cavity Cancer; Parathyroid Cancer; Penile Cancer;Pheochromocytoma; Pineoblastoma and Supratentorial PrimitiveNeuroectodermal Tumors; Pituitary Tumor; Plasma Cell Neoplasm/MultipleMyeloma; Pleuropulmonary Blastoma; Pregnancy and Breast Cancer;Pregnancy and Hodgkin's Lymphoma; Pregnancy and Non-Hodgkin's Lymphoma;Primary Central Nervous System Lymphoma; Prostate Cancer; Rectal Cancer;Renal Cell (Kidney) Cancer; Renal Pelvis and Ureter, Transitional CellCancer; Retinoblastoma; Rhabdomyosarcoma; Salivary Gland Cancer;Sarcoma, Ewing's Family of Tumors; Sarcoma, Kaposi's; Sarcoma, SoftTissue; Sarcoma, Uterine; Sezary Syndrome; Skin Cancer (non-Melanoma);Skin Cancer; Skin Cancer (Melanoma); Skin Carcinoma, Merkel Cell; SmallCell Lung Cancer; Small Intestine Cancer; Soft Tissue Sarcoma; SquamousCell Carcinoma, see Skin Cancer (non-Melanoma); Squamous Neck Cancerwith Occult Primary, Metastatic; Stomach (Gastric) Cancer;Supratentorial Primitive Neuroectodermal Tumors; T-Cell Lymphoma,Cutaneous, see Mycosis Fungoides and Sezary Syndrome; Testicular Cancer;Thymoma; Thymoma and Thymic Carcinoma; Thyroid Cancer; Transitional CellCancer of the Renal Pelvis and Ureter; Trophoblastic Tumor, Gestational;Unknown Primary Site, Carcinoma of; Unusual Cancers of Childhood; Ureterand Renal Pelvis, Transitional Cell Cancer; Urethral Cancer; UterineCancer, Endometrial; Uterine Sarcoma; Vaginal Cancer; Visual Pathway andHypothalamic Glioma; Vulvar Cancer; Waldenstrom's Macroglobulinemia;Wilms' Tumor; and Women's Cancers.

Neurologic diseases that may be treated include epilepsy, schizophrenia,bipolar disorder or other psychological and/or psychiatric disorders,neuropathies, skeletal muscle atrophy, and neurodegenerative diseases,e.g., a neurodegenerative disease. Exemplary neurodegenerative diseasesinclude: Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), andParkinson's disease. Another class of neurodegenerative diseasesincludes diseases caused at least in part by aggregation ofpoly-glutamine. Diseases of this class include: Huntington's Diseases,Spinalbulbar Muscular Atrophy (SBMA or Kennedy's Disease),Dentatorubropallidoluysian Atrophy (DRPLA), Spinocerebellar Ataxia 1(SCA1), Spinocerebellar Ataxia 2 (SCA2), Machado-Joseph Disease (MJD;SCA3), Spinocerebellar Ataxia 6 (SCA6), Spinocerebellar Ataxia 7 (SCAT),and Spinocerebellar Ataxia 12 (SCA12).

Any other disease in which the Wnt pathway, TGFβ pathway, JAK/STATpathway, the mTOR pathway, the AKT pathway, Pgp modulation, CK1, CK1γ,CK2, or PIMs plays a role may be treatable or preventable usingcompounds and methods described herein.

Exemplary Dosage

As used herein, a “therapeutically effective amount” or “therapeuticallyeffective dose” is an amount of a compound of the invention or acombination of two or more such compounds, which inhibits, totally orpartially, the progression of the condition or alleviates, at leastpartially, one or more symptoms of the condition. A therapeuticallyeffective amount can also be an amount which is prophylacticallyeffective. The amount which is therapeutically effective will dependupon the patient's size and gender, the condition to be treated, theseverity of the condition and the result sought. For a given patient, atherapeutically effective amount may be determined by methods known tothose of skill in the art.

A therapeutically effective dose refers to that amount of the compoundthat results in amelioration of symptoms in a patient. Toxicity andtherapeutic efficacy of such compounds can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the maximum tolerated dose (MTD) and the ED₅₀(effective dose for 50% maximal response). The dose ratio between toxicand therapeutic effects is the therapeutic index and it can be expressedas the ratio between MTD and ED₅₀. The data obtained from these cellculture assays and animal studies can be used in formulating a range ofdosage for use in humans. The dosage of such compounds lies preferablywithin a range of circulating concentrations that include the ED₅₀ withlittle or no toxicity. The dosage may vary within this range dependingupon the dosage form employed and the route of administration utilized.The exact formulation, route of administration and dosage can be chosenby the individual physician in view of the patient's condition. In thetreatment of crises, the administration of an acute bolus or an infusionapproaching the MTD may be required to obtain a rapid response.

Dosage amount and interval may be adjusted individually to provideplasma levels of the active moiety which are sufficient to maintain theCK1, CK1γ, CK2, Pim1-3, Wnt pathway, TGFβ pathway, JAK/STAT pathway, AKTpathway, mTOR pathway, or Pgp modulating effects, or minimal effectiveconcentration (MEC). The MEC will vary for each compound but can beestimated from in vitro data. Dosages necessary to achieve the MEC willdepend on individual characteristics and route of administration. HPLCassays or bioassays can be used to determine plasma concentrations.

Dosage intervals can also be determined using the MEC value. Compoundsshould be administered using a regimen which maintains plasma levelsabove the MEC for about 10-90% of the time, between about 30-90%, orbetween about 50-90% until the desired amelioration of symptoms isachieved. In cases of local administration or selective uptake, theeffective local concentration of the drug may not be related to plasmaconcentration.

The amount of composition administered will, of course, be dependent onthe subject being treated, on the subject's weight, the severity of theaffliction, the manner of administration and the judgment of theprescribing physician.

Exemplary Kits

The compounds and compositions of the invention (e.g., compounds andcompositions of formula 1, 2, 3, 4, 5, or 6) may, if desired, bepresented in a pack or dispenser device which may contain one or moreunit dosage forms containing the active ingredient. The pack may forexample comprise metal or plastic foil, such as a blister pack. The packor dispenser device may be accompanied by instructions foradministration. Compositions comprising a compound of the inventionformulated in a compatible pharmaceutical carrier may also be prepared,placed in an appropriate container, and labelled for treatment of anindicated condition. Instructions for use may also be provided.

EXEMPLIFICATION

The invention now being generally described, it will be more readilyunderstood by reference to the following examples, which are includedmerely for purposes of illustration of certain aspects and embodimentsof the present invention, and are not intended to limit the invention.The geometric isomers depicted below are believed to be correct, butfinal structural assignment can be made via 2-D NMR experiments.Although the exemplary compounds described below are believed to be theZ-geometric isomers, the E-geometric isomers and mixtures of the E- andZ-isomers are also contemplated by the present disclosure.

Example 1

(E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1)

1,1-dimethoxy-N,N-dimethylmethanamine (100 g, 839 mmol, 1.02 equiv.) and1,1-dimethoxypropan-2-one (97 g, 821 mmol) were added and stirred at110° C. for 3 hours. The produced methanol was removed by a Dean-Starkapparatus. After the solution was cooled to room temperature, theremaining volatile materials were removed in vacuo to provide 130 g ofthe crude product, (E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1)(130 g, 143 g theoretical, 91%). LC-MS m/z 283 (M+1). Reference: WO2006/0097341A1, pg 67.

Example 2

Sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2)

A solution of thiourea (64.7 g, 850 mmol, 1.13 equiv.), sodiummethanolate (95%, 40.5 g, 751 mmol, 1.0 equiv.) in methanol (500 mL, 1.5M) was stirred at room temperature for 30 minutes. A solution of(E)-4-(dimethylamino)-1,1-dimethoxybut-3-en-2-one (1) (130 g, 751 mmol)in methanol (200 mL) was added and the reaction stirred at roomtemperature for 2 h. The crude sodium4-(dimethoxymethyl)pyrimidine-2-thiolate (2) was used directly in thenext step without further purification. LC-MS m/z 209 (M+1). Reference:WO 2006/0097341A1, pg 67.

Example 3

4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3)

Iodomethane (128 g, 902 mmol, 1.20 equiv.) was added carefully to thecrude solution of sodium 4-(dimethoxymethyl)pyrimidine-2-thiolate (2)(156 g, 751 mmol) in methanol (700 mL, 1.1 M) while maintaining thereaction temperature below 28° C. using an ice-water bath for cooling.The resulting mixture was stirred at room temperature for 16 h. Afterremoval of the solvent under reduced pressure, the residue was dilutedwith water (300 mL) and extracted with ethyl acetate (2×150 mL). Thecombined organic layer was concentrated under reduced pressure and thecrude residue purified by passing through a short silica gel pad andwashing with diethyl ether (200 mL) to afford4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3) as a brown oil (53.7 g,150 g theoretical, 35.7%). LC-MS m/z 201 (M+1). Reference: WO2006/0097341A1, pg 67.

Example 4

2-(methylthio)pyrimidine-4-carbaldehyde (4):4-(dimethoxymethyl)-2-(methylthio)pyrimidine (3)

(53.7 g, 268 mmol) was added carefully to 1.2 N aqueous HCl (300 mL, 268mmol, 1.0 equiv.) and stirred at 60° C. for 3 hours. The reactionmixture was then cooled to room temperature and neutralized by the slowaddition of solid sodium bicarbonate. The crude mixture was extractedwith diethyl ether (3×150 mL) and the combined organic layer wasconcentrated under reduced pressure to afford2-(methylthio)pyrimidine-4-carbaldehyde (4) as a yellow solid (14.2 g,41.5 g theoretical, 34%). LC-MS m/z 155 (M+1). Reference: WO 2006/009734A1, pg 67.

Example 5

(Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(5)

A 40 mL round-bottomed vial was charged with2-(methylthio)pyrimidine-4-carbaldehyde (4) (771 mg, 5 mmol),thiazolidine-2,4-dione (586 mg, 5 mmol, 1.0 equiv.), and piperidine (400μL, 4 mmol, 0.8 equiv.) in ethanol (20 mL, 0.25 M). The reaction mixturewas heated to 80° C. and shaken for 20 h. The resulting yellowprecipitate was isolated by filtration and washed with ethanol (1×20 mL)and dried in vacuo to afford(Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(5) as a yellow solid (550 mg, 898 mg theoretical, 61%). LC-MS m/z 254(M+1).

Example 6

(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(6)

A mixture of(Z)-5-((2-(methylthio)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(5) (3.5 g, 13.82 mmol) in THF (100 mL, 0.13 M) was treated with asolution of oxone (25.8 g, 41.5 mmol, 3.0 equiv.) in water (175 mL). Theresulting mixture was stirred at room temperature for 48 h. Theresulting precipitate was filtered and washed with water (20 mL) anddiethyl ether (20 mL) to afford(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(6) as a solid (2.48 g, 3.94 g theoretical, 63%). LC-MS m/z 286 (M+1).

Example 7

General Displacement Procedure:

2-dram round bottomed vials were charged with(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(25 mg, 0.0877 mmol) prepared according to the general procedure, DMSO(1 mL, 0.08 M), diisopropylethylamine (50 μL, 0.296 mmol, 3.2 equiv.),and the appropriate amine (0.0877 mmol, 1.0 equiv.). The reactionmixture was heated to 110° C. and shaken for 24 h. The solvent wasremoved under reduced pressure (genvac HT-4) and the crude residues werepurified using reverse phase HPLC (MS-triggered fraction collection)with an acetonitrile/water gradient and trifluoroacetic acid as amodifier. The pure fractions were then concentrated under reducedpressure (Genevac (HT-4)).

Example 8 Displacement/De-Protection of Mono-Boc Diamines

General De-Protection Procedure:

The crude protected amine was prepared using the General DisplacementProcedure and was then treated with 2 mL DCE and 5004 of TFA and shakenfor 24 h. The solvent was removed under reduced pressure (Genevac HT-4)and the crude residues were purified using reverse phase HPLC(MS-triggered fraction collection) with an acetonitrile/water ormethanol/water gradient and trifluoroacetic acid as a modifier. The purefractions were then concentrated under reduced pressure (Genevac HT-4).

Example 9

General Reductive Amination Procedure 1 (Aldehydes):

A 2-dram round bottomed vial was charged with the crude amine/TFA saltprepared using the general displacement procedure followed by thegeneral TFA de-protection procedure (0.115 mmol), DCE (2 mL), DIPEA (6eq. 0.690 mmol), DMF (1 mL), the aldehyde (1 equiv., 0.115 mmol), andthe reaction mixture was shaken for 1 h at RT. The reaction mixture wasthen treated with NaBH(OAc)₃ (2.5 equiv., 0.230 mmol) and the reactionwas shaken 16 h at RT. The reaction mixture was then diluted with DCE (2mL) and NaHCO₃ (2 mL). The aqueous layer was back extracted with DCE(2×2 mL) and the combined organic layer was concentrated under reducedpressure (Genevac HT-4) and the crude residue was purified using reversephase HPLC (MS-triggered fraction collection) with an acetonitrile/wateror methanol/water gradient and triflouroacetic acid as the modifier. Thepure fractions were then concentrated under reduced pressure (GenevacHT-4) to afford the pure products as the TFA salt.

Example 10

General Reductive Amination Procedure 2 (Ketones):

A 2-dram round bottomed vial was charged with the crude amine/TFA saltprepared using the general displacement procedure followed by thegeneral TFA de-protection procedure (0.115 mmol), DCE (2 mL), DIPEA (6eq. 0.690 mmol), DMF (1 mL), the ketone (1 equiv., 0.115 mmol), and thereaction mixture was shaken for 1 h at RT. The reaction mixture was thentreated with NaBH(OAc)₃ (2.5 equiv., 0.230 mmol) and the reaction wasshaken 16 h at RT. The reaction mixture was then diluted with DCE (2 mL)and NaHCO₃ (2 mL). The aqueous layer was back extracted with DCE (2×2mL) and the combined organic layer was concentrated under reducedpressure (Genevac HT-4) and the crude residue was purified using reversephase HPLC (MS-triggered fraction collection) with an acetonitrile/wateror methanol/water gradient and triflouroacetic acid as the modifier. Thepure fractions were then concentrated under reduced pressure (GenevacHT-4) to afford the pure products as the TFA salt.

Example 11

General Procedure for the Preparation of Sulfonamides/Amides

A 2-dram round-bottomed vial was charged with the appropriate sulfonylchloride or acid chloride (0.072 mmol, 1 equiv.) in 0.5 mL of DMF, andthen treated carefully with a solution of(Z)-5-((2-(((1r,4r)-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione,prepared using the general displacement procedure followed by thegeneral de-protection procedure where appropriate, (0.072 mmol, 1equiv.), DIPEA (0.296 mmol, 4 equiv.), and 1 mL of DMF. The reactionmixture was then shaken at room temperature overnight. The reactionmixture was partitioned between 2 mL DCE and 1 mL sat. NaHCO₃ and theaqueous layer was extracted with DCE (2×2 mL). The combined organiclayer was the concentrated under reduced pressure (Genevac HT-4) and thecrude residue was purified using reverse phase HPLC (MS-triggeredfraction collection) with an acetonitrile/water or methanol/watergradient and trifluoroacetic acid as the modifier. The pure fractionswere then concentrated under reduced pressure (Genevac HT-4) to affordthe sulfonamide and amide analogs.

Example 12

(Z)-5-((2-(((1-((6-(thiophen-3-yl)pyridin-2-yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-(thiophen-3-yl)picolinaldehyde (38.8 g, 46.8 mg theoretical, 83%).LC-MS m/z 493 (M+1).

Example 13

(Z)-5-((2-(((1-((6-methylpyridin-2-yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-methylpicolinaldehyde (40.3 mg, 51.2 mg theoretical, 79%). LC-MS m/z425 (M+1).

Example 14

(Z)-5-((2-(((1-((6-fluoropyridin-2-yl)methyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-fluoropicolinaldehyde (16.2 mg, 40.7 mg theoretical, 39.8%). LC-MS m/z429 (M+1).

Example 15

(Z)-5-((2-(((1-(pyridin-3-ylmethyl)piperidin-4-yl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 andnicotinaldehyde (38.6 mg, 49.8 mg theoretical, 77%). LC-MS m/z 411(M+1).

Example 16

(Z)-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-(thiophen-3-yl)picolinaldehyde (4.5 mg, 35.5 mg theoretical, 12.7%).LC-MS m/z 493 (M+1).

Example 17

(Z)-5-((2-((trans-4-(((2-methylquinolin-4-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-methylquinoline-4-carbaldehyde (2.5 mg, 34.2 mg theoretical, 7%).LC-MS m/z 475 (M+1).

Example 18

(Z)-5-((2-((trans-4-((1-(6-(thiophen-3-yl)pyridin-2-yl)ethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 2 and1-(6-(thiophen-3-yl)pyridin-2-γ1)ethanone (3.4 mg, 36.5 mg theoretical,9%). LC-MS m/z 507 (M+1).

Example 19

(Z)-5-((2-((cis-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-(thiophen-3-yl)picolinaldehyde (4.5 mg, 35.5 mg theoretical, 12.7%).LC-MS m/z 493 (M+1).

Example 20

(Z)-5-((2-((trans-4-(((6-(thiophen-2-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-(thiophen-2-yl)picolinaldehyde (16.9 mg, 35.5 mg theoretical, 47%).LC-MS m/z 493 (M+1).

Example 21

(Z)-5-((2-((trans-4-(((2-(furan-3-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(furan-3-yl)nicotinaldehyde (4.3 mg, 34.3 mg theoretical, 12.5%).LC-MS m/z 477 (M+1).

Example 22

(Z)-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-(thiophen-3-yl)picolinaldehyde (4.5 mg, 35.5 mg theoretical, 12.7%).LC-MS m/z 493 (M+1).

Example 23

(Z)-5-((2-((trans-4-(((2-(thiophen-3-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(thiophen-3-yl)nicotinaldehyde (6.8 mg, 35.5 mg theoretical, 19.2%).LC-MS m/z 473 (M+1).

Example 24

(Z)-5-((2-((trans-4-(((2-(furan-2-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(furan-2-yl)nicotinaldehyde (5.6 mg, 34.3 mg theoretical, 16.3%).LC-MS m/z 477 (M+1).

Example 25

(Z)-5-((2-((trans-4-(((6-(furan-2-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-(furan-2-yl)picolinaldehyde (6.5 mg, 34.3 mg theoretical, 18.9%).LC-MS m/z 477 (M+1).

Example 26

(Z)-5-((2-((trans-4-((4-fluoro-2-(furan-2-γ1)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4-fluoro-2-(furan-2-γ1)benzaldehyde (1 mg, 35.5 mg theoretical, 2.8%).LC-MS m/z 494 (M+1).

Example 27

(Z)-5-((2-((trans-4-(((6-(2-(trifluoromethyl)phenyl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-(2-(trifluoromethyl)phenyl)picolinaldehyde (6.6 mg, 39.9 mgtheoretical, 16.5%). LC-MS m/z 555 (M+1).

Example 28

(Z)-5-((2-((trans-4-((3-(thiophen-2-γ1)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and3-(thiophen-2-γ1)benzaldehyde (8.6 mg, 35.4 mg theoretical, 24.3%).LC-MS m/z 492 (M+1).

Example 29

(Z)-5-((2-((trans-4-(((6-fluoronaphthalen-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-fluoro-2-naphthaldehyde (6.8 mg, 34.4 mg theoretical, 19.8%). LC-MSm/z 478 (M+1).

Example 30

(Z)-5-((2-((trans-4-(phenethylamino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-phenylacetaldehyde (4.2 mg, 30.5 mg theoretical, 13.8%). LC-MS m/z 424(M+1).

Example 31

(Z)-5-((2-((cis-4-(phenethylamino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-phenylacetaldehyde (9.5 mg, 30.5 mg theoretical, 31%). LC-MS m/z 424(M+1).

Example 32

(Z)-5-((2-((cis-4-((1-(6-(thiophen-3-yl)pyridin-2-yl)ethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 2 and1-(6-(thiophen-3-yl)pyridin-2-γ1)ethanone (2.3 mg, 36.5 mg theoretical,6%). LC-MS m/z 507 (M+1).

Example 33

(Z)-5-((2-((cis-4-(((2-methylquinolin-4-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-methylquinoline-4-carbaldehyde (3.1 mg, 34.2 mg theoretical, 9%).LC-MS m/z 475 (M+1).

Example 34

(Z)-5-((2-((trans-4-(((6-(benzo[d][1,3]dioxol-5-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-(benzo[d][1,3]dioxol-5-yl)picolinaldehyde (11.3 mg, 38.2 mgtheoretical, 30%). LC-MS m/z 531 (M+1).

Example 35

(Z)-5-((2-((trans-4-(((2-(5-(trifluoromethyl)thiophen-2-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(5-(trifluoromethyl)thiophen-2-γ1)nicotinaldehyde (3.4 mg, 40.4 mgtheoretical, 7%). LC-MS m/z 561 (M+1).

Example 36

(Z)-5-((2-((trans-4-((2-(pyridin-2-γ1)ethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(pyridin-2-γ1)acetaldehyde (2.5 mg, 44.6 mg theoretical, 1%). LC-MSm/z 425 (M+1).

Example 37

(Z)-5-((2-((trans-4-(((3-(trifluoromethyl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and3-(trifluoromethyl)picolinaldehyde (31.8 mg, 62.7 mg theoretical,50.7%). LC-MS m/z 479.5 (M+1).

Example 38

(Z)-5-((2-((trans-4-(((6-fluoroquinolin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-fluoroquinoline-2-carbaldehyde (4.3 mg, 34.5 mg theoretical, 12.5%).LC-MS m/z 479.5 (M+1).

Example 39

(Z)-5-((2-((trans-4-(((6-(furan-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-(furan-3-yl)picolinaldehyde (6.1 mg, 35.4 mg theoretical, 17%). LC-MSm/z 492 (M+1).

Example 40

(Z)-5-((2-((trans-4-(((1-bromonaphthalen-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and1-bromo-2-naphthaldehyde (1.1 mg, 38.8 mg theoretical, 2.8%). LC-MS m/z539.5 (M+1).

Example 41

(Z)-5-((2-((trans-4-((quinolin-5-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 andquinoline-5-carbaldehyde (1.1 mg, 33.2 mg theoretical, 3.3%). LC-MS m/z461.5 (M+1).

Example 42

(Z)-5-((2-((trans-4-((naphthalen-1-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and1-naphthaldehyde (4 mg, 33.1 mg theoretical, 12.1%). LC-MS m/z 460.5(M+1).

Example 43

(Z)-5-((2-((trans-4-(((6-hydroxynaphthalen-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-hydroxy-2-naphthaldehyde (3.3 mg, 34.2 mg theoretical, 9.6%). LC-MSm/z 476.5 (M+1).

Example 44

(Z)-5-((2-((trans-4-(((2′-(trifluoromethyl)-[1,1′-biphenyl]-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2′-(trifluoromethyl)-[1,1′-biphenyl]-3-carbaldehyde (8.4 mg, 39.9 mgtheoretical, 21%). LC-MS m/z 554.5 (M+1).

Example 45

(Z)-5-((2-((trans-4-(((6-methoxynaphthalen-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-methoxy-2-naphthaldehyde (3.3 mg, 35.3 mg theoretical, 9.4%). LC-MSm/z 490.5 (M+1).

Example 46

(Z)-5-((2-((trans-4-(((4′-fluoro-[1,1′-biphenyl]-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4′-fluoro-[1,1′-biphenyl]-2-carbaldehyde (8 mg, 36.3 mg theoretical,22.1%). LC-MS m/z 504.5 (M+1).

Example 47

(Z)-5-((2-((trans-4-((4-fluoro-2-(pyridin-3-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4-fluoro-2-(pyridin-3-yl)benzaldehyde (11.3 mg, 36.3 mg theoretical,31.1%). LC-MS m/z 505.5 (M+1).

Example 48

(Z)-5-((2-((trans-4-(((2-(benzofuran-2-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(benzofuran-2-yl)nicotinaldehyde (7.9 mg, 37.9 mg theoretical, 20.8%).LC-MS m/z 527.6 (M+1).

Example 49

(Z)-5-((2-((trans-4-(((2-(3-(trifluoromethoxy)phenyl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(3-(trifluoromethoxy)phenyl)nicotinaldehyde (2.6 mg, 41.1 mgtheoretical, 6.3%). LC-MS m/z 571.5 (M+1).

Example 50

(Z)-5-((2-((trans-4-(((2-(2-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(2-(trifluoromethyl)phenyl)nicotinaldehyde (2 mg, 39.9 mg theoretical,5%). LC-MS m/z 555.5 (M+1).

Example 51

(Z)-5-((2-((trans-4-(((4′-(trifluoromethyl)-[1,1′-biphenyl]-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4′-(trifluoromethyl)-[1,1′-biphenyl]-2-carbaldehyde (22.7 mg, 39.9 mgtheoretical, 50%). LC-MS m/z 554.6 (M+1).

Example 52

(Z)-5-((2-((trans-4-((2-(pyridin-4-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(pyridin-4-γ1)benzaldehyde (10.2 mg, 35 mg theoretical, 29.1%). LC-MSm/z 487.5 (M+1).

Example 53

(Z)-5-((2-((trans-4-(((2-(3-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(3-(trifluoromethyl)phenyl)nicotinaldehyde (6.4 mg, 39.9 mgtheoretical, 16%). LC-MS m/z 555.5 (M+1).

Example 54

(Z)-5-((2-((trans-4-(((2-(4-(trifluoromethyl)phenyl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(4-(trifluoromethyl)phenyl)nicotinaldehyde (5.9 mg, 39.9 mgtheoretical, 14.8%). LC-MS m/z 555.5 (M+1).

Example 55

(Z)-5-((2-((trans-4-(((5-fluoro-[1,1′-biphenyl]-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and5-fluoro-[1,1′-biphenyl]-2-carbaldehyde (6.9 mg, 36.3 mg theoretical,19%). LC-MS m/z 504.6 (M+1).

Example 56

(Z)-5-((2-((trans-4-((2-(furan-2-γ1)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(furan-2-γ1)benzaldehyde (5.4 mg, 34.2 mg theoretical, 15.8%). LC-MSm/z 476.5 (M+1).

Example 57

(Z)-5-((2-((trans-4-((2-(furan-3-γ1)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(furan-3-γ1)benzaldehyde (7.2 mg, 34.2 mg theoretical, 21%). LC-MS m/z476.5 (M+1).

Example 58

(Z)-5-((2-((trans-4-(((4-fluoronaphthalen-1-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4-fluoro-1-naphthaldehyde (6.5 mg, 34.4 mg theoretical, 18.8%). LC-MSm/z 478.3 (M+1).

Example 59

(Z)-5-((2-((trans-4-(((2′-methoxy-[1,1′-biphenyl]-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2′-methoxy-[1,1′-biphenyl]-2-carbaldehyde (12.9 mg, 37.1 mg theoretical,34.7%). LC-MS m/z 516.6 (M+1).

Example 60

(Z)-5-((2-((trans-4-(((4′-fluoro-[1,1′-biphenyl]-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4′-fluoro-[1,1′-biphenyl]-3-carbaldehyde (2.3 mg, 36.3 mg theoretical,6.3%). LC-MS m/z 504.5 (M+1).

Example 61

(Z)-5-((2-((trans-4-(((6-bromonaphthalen-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-bromo-2-naphthaldehyde (2.8 mg, 38.8 mg theoretical, 7.2%). LC-MS m/z539.5 (M+1).

Example 62

(Z)-5-((2-((trans-4-(((2-(1H-pyrazol-5-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(1H-pyrazol-5-yl)nicotinaldehyde (2.3 mg, 33 mg theoretical, 7%).LC-MS m/z 477.5 (M+1).

Example 63

(Z)-5-((2-((trans-4-((4-fluorophenethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(4-fluorophenyl)acetaldehyde (2.5 mg, 30.6 mg theoretical, 8.2%).LC-MS m/z 442.5 (M+1).

Example 64

(Z)-5-((2-((trans-4-((2-fluoro-3-(trifluoromethyl)phenethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(2-fluoro-3-(trifluoromethyl)phenyl)acetaldehyde (5.4 mg, 36.7 mgtheoretical, 15%). LC-MS m/z 510 (M+1).

Example 65

(Z)-5-((2-((trans-4-(((2-(1H-pyrrol-2-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(1H-pyrrol-2-yl)nicotinaldehyde (2.1 mg, 32.9 mg theoretical, 6.4%).LC-MS m/z 476.5 (M+1).

Example 66

(Z)-5-((2-((trans-4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-(thiophen-3-yl)picolinaldehyde (5.0 mg, 35.0 mg theoretical, 14%).LC-MS m/z 507 (M+1).

Example 67

(Z)-5-((2-((trans-4-(((2-methylpyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-methylnicotinaldehyde (7.2 mg, 29.4 mg theoretical, 24.5%). LC-MS m/z425.5 (M+1).

Example 68

(Z)-5-((2-(((trans-4-((phenethylamino)methyl)cyclohexyl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-phenylacetaldehyde (2.3 mg, 30.3 mg theoretical, 8%). LC-MS m/z 452(M+1).

Example 69

(Z)-5-((2-((trans-4-((phenethylamino)methyl)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-phenylacetaldehyde (1.6 mg, 30.2 mg theoretical, 5%). LC-MS m/z 438(M+1).

Example 70

(Z)-5-((2-((trans-4-(((4-fluoro-2-(furan-2-yl)benzyl)amino)methyl)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4-fluoro-2-(furan-2-γ1)benzaldehyde (1.3 mg, 35 mg theoretical, 3%).LC-MS m/z 508 (M+1).

Example 71

(Z)-5-((2-((trans-4-((3-(furan-2-γ1)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and3-(furan-2-γ1)benzaldehyde (11.6 mg, 32.9 mg theoretical, 35.2%). LC-MSm/z 476.5 (M+1).

Example 72

(Z)-5-((2-((trans-4-((4-fluoro-2-(thiophen-2-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4-fluoro-2-(thiophen-2-γ1)benzaldehyde (13 mg, 35.5 mg theoretical,37%). LC-MS m/z 510.6 (M+1).

Example 73

(Z)-5-((2-((trans-4-((4-fluoro-2-(thiophen-3-yl)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4-fluoro-2-(thiophen-3-γ1)benzaldehyde (17.2 mg, 35.5 mg theoretical,48.8%). LC-MS m/z 510.6 (M+1).

Example 74

(Z)-5-((2-((trans-4-((4-fluoro-2-(furan-3-γ1)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4-fluoro-2-(furan-3-γ1)benzaldehyde (10.2 mg, 20.7 mg theoretical,49.1%). LC-MS m/z 494.5 (M+1).

Example 75

(Z)-5-((2-((trans-4-(((2-methoxynaphthalen-1-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-methoxy-1-naphthaldehyde (11 mg, 33.9 mg theoretical, 32.5%). LC-MSm/z 490.5 (M+1).

Example 76

(Z)-5-((2-((trans-4-((2-(pyridin-3-γ1)benzyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(pyridin-3-γ1)benzaldehyde (9 mg, 33.7 mg theoretical, 26.7%). LC-MSm/z 487.5 (M+1).

Example 77

(Z)-5-((2-((trans-4-(((4-(dimethylamino)naphthalen-1-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4-(dimethylamino)-1-naphthaldehyde (14.4 mg, 34.8 mg theoretical,41.4%). LC-MS m/z 503.6 (M+1).

Example 78

(Z)-5-((2-(((trans-4-((((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)methyl)cyclohexyl)methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and3-(thiophen-3-γ1)benzaldehyde (3.9 mg, 34.9 mg theoretical, 11%). LC-MSm/z 521 (M+1).

Example 79

(Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione wasprepared as follows. A 40 mL round bottomed vial was charged with(Z)-5-((2-(methylsulfonyl)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(203 mg, 0.712 mmol), DMSO (3 mL), ammonium acetate (543 mg, 7.04 mmol,10 equiv.) and heated at 100° C. for 2 h. The reaction was concentratedunder reduced pressure using the Genevac. The residue was partitionedbetween 3 mL of DCE and 3 mL of H₂O and the aqueous layer was backextracted with DCE (3×3 mL). The combined organic layer was concentratedunder reduced pressure to provide the desired product. (114 mg, 0.477mmol, 67.0% yield). LC-MS m/z 223 (M+1).

Example 80

(Z)-5-((2-((3-methoxyphenyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and3-methoxyaniline (3.1 mg, 28.8 mg theoretical, 10.8%). LC-MS m/z 329(M+1).

Example 81

(Z)-5-((2-(phenylamino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and aniline (3.2mg, 26.1 mg theoretical, 12%). LC-MS m/z 299 (M+1).

Example 82

(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-γ1)furan-2-carboxamidewas prepared as follows. A 2-dram vial charged with(Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (30.4 mg,0.137 mmol), Pyridine (1.1 mL), furan-2-carbonyl chloride (107 mg, 0.821mmol, 6 equiv.), triethylamine (83 mg, 0.821 mmol, 6 equiv.), and shakenat RT. After 16 h, the reaction was treated with saturated sodiumbicarbonate (3 mL) and extracted with DCE (3×3 mL). The combined organiclayer was concentrated under reduced pressure and the residue waspurified using reverse phase HPLC to provide the desired product (14 mg,43.3 mg theoretical, 32.4%). LC-MS m/z 317.3 (M+1).

Example 83

(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-γ1)quinoline-2-carboxamidewas prepared as follows. A 2-dram vial was charged with(Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.2 mg,0.100 mmol), Pyridine (1 mL), quinoline-2-carbonyl chloride (74.6 mg,0.389 mmol, 3.8 equiv.), triethylamine (60.7 mg, 0.599 mmol, 5.9equiv.), and the reaction was shaken at RT. After 16 h, the reaction wastreated with saturated sodium bicarbonate (3 mL) and extracted with DCE(3×3 mL). The combined organic layer was concentrated under reducedpressure and the residue was purified using reverse phase HPLC toprovide the desired product (3 mg, 37.7 mg theoretical, 8%). LC-MS m/z378.4 (M+1).

Example 84

(Z)—N-(4-((2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-γ1)-5-(trifluoromethyl)picolinamidewas prepared as follows. A 2-dram vial was charged with(Z)-5-((2-aminopyrimidin-4-yl)methylene)thiazolidine-2,4-dione (22.2 mg,0.100 mmol), Pyridine (1 mL), 5-(trifluoromethyl)picolinoyl chloride (63mg, 0.301 mmol, 3 equiv.), triethylamine (60.7 mg, 0.599 mmol, 5.9equiv.), and the reaction was shaken at RT. After 16 h, the reaction wastreated with saturated sodium bicarbonate (3 mL) and extracted with DCE(3×3 mL). The combined organic layer was concentrated under reducedpressure and the residue was purified using reverse phase HPLC toprovide the desired product (4 mg, 39.5 mg theoretical, 10%). LC-MS m/z396.3 (M+1).

Example 85

(((trans-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)((6-(thiophen-3-yl)pyridin-2-yl)methyl)carbamoyl)oxy)methylacetate

(Z)-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione trifluoroacetatesalt (73.6 mg, 0.12 mmol, 1 equiv.) was dissolved in DMF (2 mL) and DIEA(63 μL, 0.36 mmol, 3 equiv.) was added at once. Chloromethylchloroformate (10.7 μL, 0.12 mmol, 1.0 equiv.) was added at once and thereaction mixture was stirred at RT for 1 h. Silver acetate (61 mg, 0.36mmol, 3 equiv.) was added at once and the reaction mixture was shakenfor 1 h at 85° C. The desired carbamate was purified by preparative HPLC(TFA method). The purest fractions were pooled and evaporated. Theresidue was re-dissolved in a 1:1 mixture of methanol/1% NH₄OH aqueoussolution and the solvents were evaporated under reduced pressure. Thefree base was purified on silica gel (CH₂Cl₂/MeOH 95:5) to give thedesired product as a yellow solid (1.1 mg, 73.7 mg theoretical, 1.5%).LC-MS m/z 609 (M+1).

Example 86

((Z)-5-((2-(((1s,4s)-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyldihydrogen phosphate

An 8 mL round bottomed vial was charged with boc-protected amine[sad123-119] (34.5 mg, 46 μmol., 1 equiv.), CH₂Cl₂ (0.5 mL), and TFA(175 μL, 2.28 mmol., 50 equiv.). The solution was stirred for 15 min atRT. LC-MS showed the reaction was complete. The solvents wereconcentrated under reduced pressure. The residue was dissolved in DMSOand purified by revers phase HPLC (0-50, 12 min, 2 inj) to provide 18.3mg (73.8%, 1 TFA salt) of the desired product as a white solid. LC-MS:0.58 min, M+1=430.

Example 87

(Z)-5-((2-(((1r,4r)-4-((((6-fluoronaphthalen-2-yl)methyl)amino)methyl)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-fluoro-2-naphthaldehyde (2.4 mg, 23.9 mg theoretical, 7%). LC-MS m/z492.5 (M+1).

Example 88

(Z)-5-((2-(((1r,4r)-4-(((2-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-(2,2,2-trifluoroethoxy)nicotinaldehyde (6.7 mg, 35.5 mg theoretical,19%). LC-MS m/z 509.5 (M+1).

Example 89

(Z)-5-((2-(((1r,4r)-4-(((5-fluoro-2-methoxypyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and5-fluoro-2-methoxynicotinaldehyde (4.3 mg, 31.7 mg theoretical, 13.5%).LC-MS m/z 459.5 (M+1).

Example 90

(Z)-5-((2-(((1r,4r)-4-(((2-methoxypyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-methoxynicotinaldehyde (9.3 mg, 30.5 mg theoretical, 30.5%). LC-MS m/z441.5 (M+1).

Example 91

(Z)-5-((2-(((1r,4r)-4-(((2-fluoropyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-fluoronicotinaldehyde (13.1 mg, 29.7 mg theoretical, 44%). LC-MS m/z429.5 (M+1).

Example 92

(Z)-5-((2-(((1r,4r)-4-((pyridin-3-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 andnicotinaldehyde (3.7 mg, 38.6 mg theoretical, 10%). LC-MS m/z 411 (M+1).

Example 93

(Z)-5-((2-(((1r,4r)-4-((benzofuran-5-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 andbenzofuran-5-carbaldehyde (4.6 mg, 42.2 mg theoretical, 10%). LC-MS m/z450.5 (M+1).

Example 94

(Z)-5-((2-(((1r,4r)-4-(((4-chloropyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4-chloronicotinaldehyde (3 mg, 42 mg theoretical, 7%). LC-MS m/z 446(M+1).

Example 95

(Z)-5-((2-(((1r,4r)-4-(((6-hydroxypyridazin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and6-hydroxypyridazine-3-carbaldehyde (6.8 mg, 40.2 mg theoretical, 17%).LC-MS m/z 428 (M+1).

Example 96

(Z)-5-((2-(((1r,4r)-4-((quinolin-8-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 andquinoline-8-carbaldehyde (2.1 mg, 43.3 mg theoretical, 4.8%). LC-MS m/z461 (M+1).

Example 97

(Z)-5-((2-(((1r,4r)-4-(((4-(furan-3-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4-(furan-3-yl)nicotinaldehyde (14.6 mg, 44.8 mg theoretical, 32%). LC-MSm/z 477 (M+1).

Example 98

(Z)-5-((2-(((1r,4r)-4-((pyrimidin-5-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 andpyrimidine-5-carbaldehyde (23.3 mg, 48.7 mg theoretical, 60%). LC-MS m/z412 (M+1).

Example 99

(Z)-5-((2-(((1r,4r)-4-(((2-fluoro-4-(furan-3-yl)pyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and2-fluoro-4-(furan-3-yl)nicotinaldehyde (17 mg, 46.5 mg theoretical,37%). LC-MS m/z 495 (M+1).

Example 100

(Z)-5-((2-(((1r,4r)-4-(((4-methoxypyridin-3-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and4-methoxynicotinaldehyde (21 mg, 41.4 mg theoretical, 51%). LC-MS m/z441 (M+1).

Example 101

(Z)-5-((2-(((1r,4r)-4-((isoquinolin-4-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 andisoquinoline-4-carbaldehyde (27.9 mg, 44.3 mg theoretical, 64.5%). LC-MSm/z 461 (M+1).

Example 102

N-((1r,4r)-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)quinoline-8-sulfonamidewas prepared using the General Procedure for the Preparation ofSulfonamides/Amides and quinoline-8-sulfonyl chloride (6.6 mg, 80 mgtheoretical, 8.3%). LC-MS m/z 511.5 (M+1).

Example 103

N-((1r,4r)-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)quinoline-8-carboxamidewas prepared using the General Procedure for the Preparation ofSulfonamides/Amides and quinoline-8-carbonyl chloride (6.8 mg, 44.6 mgtheoretical, 15.3%). LC-MS m/z 475.5 (M+1).

Example 104

N-((1r,4r)-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)furan-2-carboxamidewas prepared using the General Procedure for the Preparation ofSulfonamides/Amides and furan-2-carbonyl chloride (8.9 mg, 38.8 mgtheoretical, 23%). LC-MS m/z 414 (M+1).

Example 105

N-((1r,4r)-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)furan-2-sulfonamidewas prepared using the General Procedure for the Preparation ofSulfonamides/Amides and furan-2-sulfonyl chloride (7 mg, 70.7 mgtheoretical, 10%). LC-MS m/z 450.5 (M+1).

Example 106

(Z)-5-((2-(((1r,4r)-4-aminocyclohexyl)(methyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl((1r,4r)-4-(methylamino)cyclohexyl)carbamate followed by the generalde-protection procedure (2.5 mg, 23.3 mg theoretical, 10%). LC-MS m/z334 (M+1).

Example 107

(Z)-5-((2-(methyl((1r,4r)-4-((naphthalen-1-ylmethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general reductive amination procedure 1 and1-naphthaldehyde (5.4 mg, 42.3 mg theoretical, 13%). LC-MS m/z 474.5(M+1).

Prophetic Reductive Amination Analogs (Some Syntheses Completed)

Example 108

(Z)-5-((2-((trans-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl(trans-4-aminocyclohexyl)carbamate followed by the general de-protectionprocedure (6.3 mg, 8.9 mg theoretical, 70%). LC-MS m/z 320 (M+1).

Example 109

(Z)-5-((2-((cis-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl(cis-4-aminocyclohexyl)carbamate followed by the general de-protectionprocedure (17 mg, 15.2 mg theoretical, 112%). LC-MS m/z 320 (M+1).

Example 110

(Z)-5-((2-((trans-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and tert-butyl((trans-4-aminocyclohexyl)methyl)carbamate followed by the generalde-protection procedure (5.6 mg, 6.15 mg theoretical, 91%). LC-MS m/z334 (M+1).

Example 111

(Z)-5-((2-((4-morpholinophenyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure and4-morpholinoaniline (2 mg, 33.6 mg theoretical, 6%). LC-MS m/z 384(M+1).

Example 112

N-(trans-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)furan-2-carboximidamidewas prepared as follows.

Preparation of methyl furan-2-carbimidate hydrochloride

A 30 mL scintillation vial was charged with furan-2-carbonitrile (107mg, 1.15 mmol), methanol (1 mL), and 4.0 M HCl in dioxane (2 mL, 8.00mmol, 6.95 equiv.). The reaction was shaken at room temperatureovernight. LCMS showed a predominant peak for M+1=126, methylfuran-2-carbimidate. The solvent was evaporated under reduced pressureand the material was used directly in the next step without furtherpurification.

A 2-dram round botommed vial was charged with methyl furan-2-carbimidatehydrochloride (14.5 mg, 0.090 mmol), DMSO (0.5 mL),(Z)-5-((2-((trans-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione(27.2 mg, 0.085 mmol) (prepared using the general displacement procedureand tert-butyl ((1R,4R)-4-aminocyclohexyl)carbamate followed by thegeneral de-protection procedure), MeOH (0.25 mL) was then added and themixture shaken until homogeneous. The solution was then treated withN-ethyl-N-isopropylpropan-2-amine (250 mg, 1.934 mmol, 21.5 equiv.),purged with Ar, capped and shaken overnight at room temperature. (8.4mg, 35.1 mg theoretical, 23.9%). LC-MS m/z 413 (M+1).

Example 113

(Z)-5-((2-((trans-4-((2-(2-methoxyethoxy)ethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared as follows. Synthesis oftrans-N1-(2-(2-methoxyethoxy)ethyl)cyclohexane-1,4-diamine bistrifluoroacetic acid salt

2-(2-Methoxyethoxy)ethyl 4-methylbenzenesulfonate

A solution of 2-(2-methoxyethoxy)ethanol (200 mg, 1.67 mmol, 1 equiv.),triethylamine (232 μL, 1.67 mmol, 1.0 equiv.) and tosyl chloride (317mg, 1.67 mmol., 1 equiv.) in methylene chloride (5 mL, 0.29 M) wasstirred at room temperature for 50 hours. After removal of the solventunder reduced pressure, the residue was purified by chromatography onsilica gel (10 g, hexanes/EtOAc 9:1 to 1:1) to afford(2-methoxyethoxy)ethyl 4-methylbenzenesulfonate as a colorless oil (260mg, 457 mg theoretical, 56.9%). LC-MS m/z 275 (M+1).

tert-Butyl(trans-4-((2-(2-methoxyethoxy)ethyl)amino)cyclohexyl)carbamate

A solution of (2-methoxyethoxy)ethyl 4-methylbenzenesulfonate (160 mg,0.58 mmol, 1 equiv.), DIEA (102 μL, 0.58 mmol, 1.0 equiv.) andtert-butyl (trans-4-aminocyclohexyl)carbamate (125 mg, 0.58 mmol., 1equiv.) in acetonitrile (2.5 mL, 0.23 M) was stirred at 85° C. for 50minutes. After removal of the solvent under reduced pressure, theresidue was purified by preparative HPLC (H₂O/MeOH 0.1% TFA) to affordtert-butyl(trans-4-((2-(2-methoxyethoxy)ethyl)amino)cyclohexyl)carbamatetrifluroacetate salt as a colorless oil (114 mg, 251 mg theoretical,45.4%). LC-MS m/z 317 (M+1), 275 (M+1-isobutylene).

Synthesis of trans-N1-(2-(2-methoxyethoxy)ethyl)cyclohexane-1,4-diaminebis trifluoroacetate salt

A solution of tert-butyl(trans-4-((2-(2-methoxyethoxy)ethyl)amino)cyclohexyl)carbamatetrifluroacetate salt (114 mg, 0.27 mmol, 1 equiv.) in TFA (1.38 mL, 18.0mmol, 68.0 equiv.) and methylene chloride (1.5 mL, 0.09 M) was stirredat RT for 1 hour. After removal of the solvent under reduced pressure,the residue was triturated in ether to affordtrans-N1-(2-(2-methoxyethoxy)ethyl)cyclohexane-1,4-diamine bistrifluoroacetate salt as a white solid (77.7 mg, 118 mg theoretical,66.0%). LC-MS m/z 217 (M+1).

(Z)-5-((2-((trans-4-((2-(2-methoxyethoxy)ethyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dionewas prepared using the general displacement procedure andtrans-N1-(2-(2-methoxyethoxy)ethyl)cyclohexane-1,4-diamine bistrifluoroacetate salt (4.1 mg, 56.3 mg theoretical, 7.3%). LC-MS m/z 422(M+1).

Example 114 Prophetic Prodrug Analogs

Example 115

((Z)-5-((2-(((1s,4s)-4-aminocyclohexyl)amino)pyrimidin-4-yl)methylene)-2,4-dioxothiazolidin-3-yl)methyldihydrogen phosphate

tert-butyl(trans-4-((4-((Z)-(2,4-dioxothiazolidin-5-ylidene)methyl)pyrimidin-2-yl)amino)cyclohexyl)carbamatetrifluoroacetate salt (70.8 mg, 0.13 mmol, 1 equiv.) is dissolved in DMF(1 mL) and sodium hydride 60% in mineral oil (63 μL, 0.36 mmol, 3equiv.) is added at once. Chloromethyl chloroformate (10.6 mg, 0.26mmol, 2.0 equiv.) is added at once and the reaction mixture is stirredat RT for 45 min. di-tert-Butyl (chloromethyl) phosphate (31 μL, 0.13mmol, 1 equiv.) is added at once and the reaction mixture is shaken for1 h at RT. The reaction mixture is then shaken at 50° C. The solvent isevaporated and the residue is suspended in CH₂Cl₂ and treated withtrifluoroacetic acid (0.26 mL, 3.33 mmol, 25 equiv). The desiredphosphate is purified by preparative HPLC (Basic method).

Example 116

((Z)-2,4-dioxo-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidin-3-yl)methyldihydrogen phosphate

((Z)-2,4-dioxo-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidin-3-yl)methyldihydrogen phosphate is prepared by boc-protecting the secondary amineof(Z)-5-((2-((trans-4-(((6-(thiophen-3-yl)pyridin-2-yl)methyl)amino)cyclohexyl)amino)pyrimidin-4-yl)methylene)thiazolidine-2,4-dione followed by thealkylation of the hydantoin with di-tert-butyl chloromethylphosphate andthe deprotection of the t-butyl groups and the boc group with TFA.

Example 117 General Boronic Acid Coupling Procedures for the Synthesisof Custom Aldehydes

A 2-dram round bottomed vial was charged with 6-bromopicolinaldehyde(100 mg, 0.538 mmol) and the boronic acid (0.538 mmol, 1 equiv.) wereadded in THF (2 mL). Then 2 M Na₂CO₃ (0.403 mL, 0.806 mmol, 1.5 equiv.)and Pd(Ph₃P)₄ (31.0 mg, 0.027 mmol, 0.05 equiv.) were added and shakenat 85° C. overnight. The solvent was removed in the genevac and theresidue was washed with saturated NaHCO₃ (1 mL). The aqueous layer wasextracted with EtOAc (3×1 mL). The combined organic layers were dried onthe genevac and the crude was purified using flash purification with agradient of 5-40% EtOAc in hexane.

General Boronic Acid Coupling Procedures for the Synthesis of CustomKetones

A 40 mL round bottomed vial was charged with1-(6-bromopyridin-2-γ1)ethanone (780 mg, 3.9 mmol), THF (96 mL, 0.48 M),the boronic acid (3.9 mmol, 1.0 equiv.), 2 M Na₂CO₃ (3.9 mL, 7.8 mmol,2.0 equiv.), Pd(Ph₃P)₄ (225 mg, 0.195 mmol, 0.05 equiv.), purged withAr, and shaken at 85° C. for 36 h. The solvent was removed in thegenevac and the residue was partitioned between saturated NaHCO₃ (25 mL)and EtOAc (25 mL). The aqueous layer was extracted with EtOAc (3×20 mL).The combined organic layer was dried over Na₂SO₄ and concentrated underreduced pressure. The crude material was purified on the Biotage (SiO₂,50 g, 2-50% EtOAc/hexanes over 30 column volumes) to afford the desiredcoupled products.

Example 118—Assays Selected Cell Proliferation Inhibition Data

TABLE 1 Human Positive Incubation cancer Cell line Medium drug timeMultiple MV4-11 IMDM Cisplatin 72 hours Myeloma RPMI-8226 RPMI-1640NCI-H929 RPMI-1640 + 0.05 mM 2-mercaptoethanol

All cells were cultured in media supplemented with 10% FBS except forwhich are marked specially, in the temperature of 37° C., 5% CO₂ and 95%humidity. All culture media were purchased from GIBCO (USA, IMDM Cat.12200-036; RPMI Medium 1640 Cat.31800-022; 2-mercaptoethanol Cat.21985-023).

Reagents:

CellTiter 96® Aqueous MTS reagent powder (Cat. No.: G11 12, Promega.Store MTS Reagent Powder desiccated at 4° C. protected from light.)Phenazine methosulfate (PMS) (Product No.: P9625, SIGMA. Store PMSPowder desiccated at 4° C. protected from light.)

Preparation of PMS solution

0.92 mg/mL PMS in DPBS Filter-sterilize through a 0.2 μm filter into asterile, light-protected container. Store at −20° C.

Preparation of MTS solution

The following protocol is recommended for the preparation of 21 mL ofMTS solution (sufficient for ten 96-well plates).

-   a. Select a light-protected container or wrap a container with foil.-   b. Add 21 mL of DPBS to the container.-   c. Weigh out 42 mg of MTS Reagent Powder and add to DPBS.-   d. Mix at moderate speed on a magnetic stir plate for 15 minutes or    until the MTS is completely dissolved.-   e. Measure the pH of the MTS solution. The optimum pH is between pH    6.0 to 6.5. If the solution is above pH 6.5, adjust to pH 6.5 with    1N HCl.-   f. Filter-sterilize the MTS solution through a 0.2 μm filter into a    sterile, light protected container.-   g. Store the MTS solution at −20° C., protected from light.

Preparation of the mixture of MTS/PMS

-   a. In order to prepare reagents sufficient for one 96-well plate    containing cells cultured in a 100 μL volume, thaw the MTS solution    and the PMS solution. It should take approximately 90 minutes at    room temperature or 10 minutes in a 37° C. water bath to completely    thaw the 20 mL size of MTS solution. (Note: For convenience, the    first time the product is thawed, the entire contents of the 1 mL    tube of PMS solution can be transferred to the 20 mL bottle of MTS    solution. This mixture should be stored at −20° C. between uses. If    storing PMS and MTS solutions at 4° C., do not combine these    solutions until immediately before addition to the assay plate.)-   b. Remove 2.0 mL of MTS solution from the amber reagent bottle using    aseptic technique and transfer to a test tube.-   c. Add 100 μL of PMS solution to the 2.0 mL of MTS solution    immediately before addition to the culture plate containing cells.-   d. Gently swirl the tube to ensure complete mixing of the combined    MTS/PMS solution.

Equipment:

SpectraMAX plus microplate spectrophotometer Model 3011, MolecularDevices Corp. (California, USA); CO₂ water jacketed incubator, Therma(USA). Reverse microscope, Chongguang XDS-1B, Chongqing Guangdian Corp.(Chongqing, P.R.China).

Cytotoxicity and IC₅₀ determination:

-   1. The cells were harvested respectively during the logarithmic    growth period and counted with hemocytometer. The cell viability was    over 98% by trypan blue exclusion.-   2. Cell concentrations were adjusted to 2.22×113 or 1.11×113 or    5.56×10⁴ cells/mL with respective medium.-   3. 90 μL cell suspensions were added to 96-well plates (triplicates    for each cell concentration), the final cell densities were 2×10⁴ or    1×10⁴ or 5×10³ cells/well. The density of 5×10³ cells/well was used    for the first test. The appropriate cell density was determined and    adjusted according to the results of the first test.-   4. The next day, test article or positive drugs were dissolved with    DMSO as stock solution at the concentration of 20 mM.-   5. 10 μL drug solution was dispensed in each well (triplicate for    each drug concentration).-   6. Plates were cultured for another 72 hours, then measured by means    of MTS assay.-   7. MTS/PMS solution was prepared immediately prior to use. 20 μL of    the mixture was introduced into each well of the 96-well assay plate    containing 100 μL culture medium. (The final reaction volume was 120    μL).-   8. Plate was incubated for 1-4 hours at 37° C. in a humidified 5%    CO₂ atmosphere.-   9. Absorbance at 490 nm was recorded using SpectraMAX Plus    microplate spectrophotometer.

Data Analysis:

The software of GraphPad Prism version 5 was used to calculate IC₅₀. Thegraphical curves were fitted using a nonlinear regression model with asigmoidal dose.

Results

Results are shown in Table 2.

TABLE 2 IC₅₀ values (μM) RPMI- Cmpd Panc-1 8226 KU812 NCl-H929 MV4-1111219 >50 18 >50 17.1 11231 32 21.4 >50 10.8 11233 27 14.1 6.7 35 1123811.5 3.2 11.8 2.1 11239 18.1 2.2 23.5 3.2 11252 >50 >50 >50 27.411253 >50 41 >50 16.2 11254 >50 >50 >50 33.4 11255 5.3 2.6 2.1 0.55 0.4211256 15.7 8.6 19.4 7.2 11270 5.6 1.8 2.5 0.64 0.7 11292 >50 >50 1129427 28 11302 36.9 14.3 11305 2.7 1.2 11353 7.4 10.4 11405 0.91 1 11407 11.1 11408 1.5 1.4 11409 0.93 1.2 11410 1.9 2.3 11412 1.1 1.2 11413 0.730.55 0.59 0.54 11414 0.58 0.29 11415 1.1 1.4 11416 0.11 0.13 0.23 0.08511417 3.4 1.8 11421 4.3 1.9 11422 5.1 3.3 11423 15.3 4.1 11406 2.9 7.411411 2.6 18.8 11533 29.1 >50 11534 1.1 10.2 11535 0.67 5.3 11536 1.42.7 11432 0.92 3.2 11644 0.062 0.11 0.086 0.037 11645 2.7 1.7 116460.091 0.031 11647 1.4 2.3 11648 4.8 3.6 11649 2.1 1.9 11650 0.66 1.511651 >50 6.8 11652 0.35 0.34 11653 >50 7.6 11654 1.6 6.3 11655 5.2 4.711656 2.3 11657 1.3 5.3 11658 0.3 1 11659 7 4.7 11660 0.77 0.4 0.2411661 1.5 1.1 11662 0.082 0.14 0.084 0.1 11663 2.4 2.1 11664 3.7 4.511665 4 0.98 11669 18.2 18.4 11670 10.3 9.8 11671 0.8 1.4 11672 1.2 1.411673 0.2 0.33 11674 3.5 3.3 11675 4.6 1.6 11676 0.93 1.2 11677 1.2 1.711678 0.69 0.76 11723 21 14 11712 4.2 4 11717 0.55 1.1 11739 3.4 3.911740 5.5 4.4 11741 4.6 4.2 11801 3.9 3.5 11802 0.49 0.16 0.097 118163.4 0.34 0.38 11834 >50 >50 11835 4.7 1.3 11836 10.1 0.65 11837 >50 311838 >50 4.6 11839 >50 11.8 11840 1.5 0.37

TABLE 3 Percent Activity of Enzyme When Treated with 300 nM of Compound(ATP present at Km of enzyme) CK1γ2 CK1 CK2 Pim-1 Pim-2 Pim-3 Cmpd (h)(y) (h) (h) (h) (h) 11219 64 63 10 23 3 5 11231 113 92 10 50 58 42 1123397 64 80 100 99 91 11238 48 61 14 52 42 32 11239 52 91 21 56 37 33 1125296 96 20 86 110 83 11253 101 93 68 99 55 96 11254 96 107 86 113 97 11311255 14 46 16 15 1 7 11256 44 58 30 26 2 4 11270 25 59 32 19 1 5 1129245 77 11 14 −1 3 11294 87 72 32 35 4 5 11302 98 82 12 12 3 3 11305 71 8611 22 6 8 11353 43 50 12 18 −1 4 11405 −6 18 −1 8 −2 0 11407 53 48 −7 10−1 0 11408 7 43 5 12 1 3 11409 54 41 −11 11 0 2 11410 77 74 −12 21 −1 011412 22 49 14 11 −1 0 11413 38 62 −16 7 0 2 11414 25 42 20 18 0 1 114156 35 −5 11 −1 1 11416 19 48 −9 7 −1 0 11417 57 55 6 14 0 0 11421 98 97 832 3 2 11422 79 97 49 78 15 25 11423 98 99 46 49 8 8 11406 −10 44 25 145 3 11411 43 52 76 28 0 12 11533 109 80 63 46 7 6 11534 72 59 21 14 −1 211535 35 51 14 14 −1 1 11536 31 84 64 44 2 9 11432 12 47 16 16 1 6 1164413 57 −3 10 1 5 11645 29 45 −19 3 0 2 11646 22 56 −15 7 1 2 11647 9 35−18 7 1 6 11648 −2 41 15 28 2 21 11649 5 37 −15 5 0 1 11650 9 51 −3 14 04 11651 55 71 1 22 −1 3 11652 17 50 −6 16 0 5 11653 33 52 26 21 1 511654 63 67 −10 19 3 2 11655 14 67 54 34 1 16 11656 65 75 −6 20 −1 111657 23 39 29 35 2 2 11658 6 30 19 13 1 1 11659 9 37 −6 9 −2 1 11660 4058 −14 11 −2 2 11661 −3 32 −17 9 −3 −1 11662 16 52 −14 9 −2 −2 11663 2554 1 12 −2 −1 11664 5 39 1 19 −2 −1 11665 14 52 9 20 −2 3 11669 77 80 −616 1 3 11670 74 86 46 48 7 10 11671 28 50 23 16 2 4 11672 31 40 −6 14 03 11673 5 19 −2 11 1 2 11674 72 65 −12 10 0 2 11675 82 77 −11 18 18 1111676 32 49 −10 11 2 3 11677 21 47 0 20 4 6 11678 −4 41 −18 6 −1 2 1167927 43 −6 9 0 3 11680 24 35 −11 7 0 2 11681 23 44 −13 10 −1 4 11682 29 54−18 10 −1 1 11683 50 62 −6 12 −1 2 11684 41 58 −12 5 −1 2 11685 98 95 95119 103 89 11686 46 68 38 17 12 22 11536 31 84 64 44 2 9 11723 63 78 −1523 0 4 11712 −1 25 −6 11 2 4 11717 43 50 −16 15 0 2 11739 63 78 −15 23 04 11740 62 67 −17 18 −2 6 11741 48 68 −14 17 0 6 11801 72 66 1 19 −2 311802 27 56 −3 7 −2 3 11816 38 46 −4 8 −2 1 11834 76 70 11 20 −3 2 1183549 73 2 13 −6 2 11836 41 56 7 14 −5 2 11837 71 57 16 19 −6 2 11838 32 555 20 −6 1 11839 69 55 −1 16 −6 −1 11840 37 48 −5 11 −8 −1 12040 −3 −1 012054 −2 −3 0 12078 19 −1 2

TABLE 4 IC₅₀ (nM) (ATP present at Km of enzyme) CK1γ2 CK1 CK2 Pim-1Pim-2 Pim-3 Cmpd (h) (y) (h) (h) (h) (h) 11219 204 7 27 11231 72 1123311238 69 11239 87 11252 61 11255 12 0.5 4 11256 123 1 15 11270 187 3 3211292 69 78 1 9 11294 247 18 113 11407 33 0.6 3 11409 103 1 4 11410 1081 9 11413 9 38 0.6 9 11414 85 2 5 11416 29 36 1 6 11417 42 2 4 11644 4532 0.7 6 11646 6 24 0.5 1 11650 29 68 2 12 11652 24 67 0.7 16 11660 1142 2 4 11662 6 50 9 4 11673 28 96 4 18 11674 11 79 0.7 5 11923 377 160205 11932 1231 6 260 11933 330 11 26 11934 118 10 14 12054 82 29 1 7

INCORPORATION BY REFERENCE

All of the U.S. patents and U.S. published patent applications citedherein are hereby incorporated by reference.

EQUIVALENTS

While several embodiments of the present invention have been describedand illustrated herein, those of ordinary skill in the art will readilyenvision a variety of other means and/or structures for performing thefunctions and/or obtaining the results and/or one or more of theadvantages described herein, and each of such variations and/ormodifications is deemed to be within the scope of the present invention.More generally, those skilled in the art will readily appreciate thatall parameters, dimensions, materials, and configurations describedherein are meant to be exemplary and that the actual parameters,dimensions, materials, and/or configurations will depend upon thespecific application or applications for which the teachings of thepresent invention is/are used. Those skilled in the art will recognize,or be able to ascertain using no more than routine experimentation, manyequivalents to the specific embodiments of the invention describedherein. It is, therefore, to be understood that the foregoingembodiments are presented by way of example only and that, within thescope of the appended claims and equivalents thereto, the invention maybe practiced otherwise than as specifically described and claimed. Thepresent invention is directed to each individual feature, system,article, material, kit, and/or method described herein. In addition, anycombination of two or more such features, systems, articles, materials,kits, and/or methods, if such features, systems, articles, materials,kits, and/or methods are not mutually inconsistent, is included withinthe scope of the present invention.

1-38. (canceled)
 39. A compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 40. The compound of claim39, wherein the compound is selected from the group consisting of:


41. The compound of claim 39, wherein the compound is selected from thegroup consisting of:


42. The compound of claim 39, wherein the compound is selected from thegroup consisting of


43. The compound of claim 39, wherein the compound is selected from thegroup consisting of


44. The compound of claim 39, wherein the compound is selected from thegroup consisting of


45. The compound of claim 39, wherein the compound is


46. The compound of claim 39, wherein the compound is


47. The compound of claim 39, wherein the compound is


48. The compound of claim 39, wherein the compound is


49. The compound of claim 39, wherein the compound is


50. The compound of claim 39, wherein the compound is


51. A pharmaceutical composition, comprising a pharmaceuticallyacceptable carrier; and a compound selected from the group consistingof:

or a pharmaceutically acceptable salt thereof.
 52. The pharmaceuticalcomposition of claim 51, wherein the compound is


53. The pharmaceutical composition of claim 51, wherein the compound is


54. The pharmaceutical composition of claim 51, wherein the compound is


55. The pharmaceutical composition of claim 51, wherein the compound is


56. The pharmaceutical composition of claim 51, wherein the compound is


57. The pharmaceutical composition of claim 51, wherein the compound is